Phosphorous derivatives as kinase inhibitors

ABSTRACT

The invention features compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.

BACKGROUND OF THE INVENTION

The protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processesand maintain control over cellular function. A partial, non limiting,list of such kinases includes ALK, abl, Akt, bcr-abl, Blk, Brk, c-kit,c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9,CDK10, bRaf, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, flt-3, Fps, Frk, Fyn,Hck, IGF-1R, INS-R, Jak1, Jak2, Jak3, KDR, Lck, Lyn, FAK, MEK, p38,PDGFR, PIK, PKC, PYK2, ros, tie, tie2, Pim-1, Pl3k,TRK and Zap70.Abnormal protein kinase activity has been related to several disorders,ranging from non-life threatening diseases such as psoriasis toextremely serious diseases such as cancers.

In view of this large number of protein kinases and the multitude ofprotein kinase-related diseases, there is an ever-existing need toprovide new classes of compounds with increased selectivity that areuseful as protein kinase inhibitors and therefore useful in thetreatment of protein tyrosine-kinase related diseases.

The invention concerns a new family of phosphorous compounds and theiruse in treating cancers and other diseases.

DESCRIPTION OF THE INVENTION 1. General Description of Compounds of theInvention

Compounds of the invention can have a broad range of useful biologicaland pharmacological activities, permitting their use in pharmaceuticalcompositions and methods for treating cancer (including lymphoma, solidtumors and leukemia among other cancers), including, also among others,advanced cases and cases which are resistant or refractory to one ormore other treatments.

Included are compounds of Formula I, and tautomers and pharmaceuticallyacceptable salts and solvate thereof:

wherein

X¹ is NR^(b1) or CR^(b);

X² is NR^(c1) or CR^(c);

X³ is NR^(d1) or CR^(d);

X⁴ is NR^(e1) or CR^(e);

Ring A is an aryl, a 5- or a 6-membered heteroaryl ring which contains 1to 4 heteroatoms selected from N, O and S(O)_(r);

at each occurrence R^(a), R^(b), R^(c), R^(d) and R^(e) areindependently selected from the group consisting of halo, —CN, —NO₂,—R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃,

—NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R², and R^(b1), R^(c1),R^(d1) and R^(e1) are absent; wherein each Y is independently a bond,—O—, —S— or —NR¹—; or

alternatively two adjacent substituents selected from R^(b), R^(b1),R^(e), R^(c1), R^(d), R^(d1), R^(e) and R^(e1); or two adjacent R^(a)moieties, can form with the atoms to which they are attached a 5-, 6- or7-membered saturated, partially saturated or unsaturated ring, whichcontains 0-4 heteroatoms selected from N, O and S(O)_(r) and which issubstituted with one to four R^(f) moities wherein;

each R^(f) moiety is independently selected from the group consisting ofhalo, ═O, =S, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R²,—NR¹—OR², —C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR²,—OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR²,—YP(═O)(YR³)(YR³), —Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and—NR¹SO₂NR¹R²; or alternatively two adjacent R^(f) moieties can form withthe atoms to which they are attached a 5-, 6- or 7-membered saturated,partially saturated or unsaturated ring, optionally substituted; andwhich contains 0-4 heteroatoms selected from N, O and S(O)_(r);

at least one of R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(b1),R^(c1), R^(d1) and R^(e1) when present, is or contains —P(═O)(R³)₂ or aring system containing the moiety —P(═O)(R³)— as a ring member.

r is 0, 1 or 2;

s is 1, 2, 3, 4 or 5

n is 0 or 1;

each occurrence of Y is independently a bond, —O—, —S— or —NR¹—;

each occurrence of R¹ and R² is independently selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl;

each occurrence of R³ is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic and heteroaryl, or two adjacent R³ moieties combine to forma ring system including a phosphorous atom;

each occurrence of R^(3a) is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic, and heteroaryl;

alternatively, each NR¹R² moiety may be a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which can beoptionally substituted and which contains 0-2 additional heteroatomsselected from N, O and S(O)_(r); and

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl and heterocyclic moiety is optionallysubstituted.

The foregoing definitions are further elaborated upon and exemplifiedbelow and apply to all subsequent occurrences except to the extentotherwise specified.

2. Featured Classes of Compounds and their Use, Generally

One class of compounds which is of special interest for use in theinvention are compounds of Formula I, as described above in Part 1, inwhich X² is CR^(c), X³ is CR^(d) and X⁴ is CR^(e). This class isillustrated by compounds of Formula IA:

wherein

X¹ is N or CR^(b); and Ring A, R^(a), R^(b), R^(c), R^(d), R^(e), n, ands are as defined in Formula I. One class of interest includes compoundsin which Ring A is a phenyl.

Another class of interest includes compounds in which Ring A is a 5- or6-membered heteroaryl.

Another class of compounds which is of special interest for use in theinvention are compounds of Formula Ia, as described above, in which X¹is CR^(b).

This class is illustrated by compounds of Formula IB:

A subclass of interest include compound of Formula IB in which n is 0.

Another subclass of interest includes compounds of Formula IB in which nis 1.

Another subclass of interest includes compounds of Formula IB in whichRing A is phenyl.

Of special interest is another class of compounds of Formula IA asdescribed above in Part 1 in which X¹ is N. This class is illustrated bycompounds of Formula IC:

A subclass of interest include compound of Formula IC in which n is 0.

Another subclass of interest includes compounds of Formula IC in which nis 1.

Another subclass of interest includes compounds of Formula IC in whichRing A is phenyl.

In Formulas IB and IC, s, R^(a), R^(b), R^(c), R^(d) and R^(e) are asdefined above in Formula I. In a particular embodiment of the previousclasses and subclasses, one of R^(a) is or contains a —P(═O)(R³)₂ group.Examples of R^(a) containing a —P(═O)(R³)₂ group include, withoutlimitation, —(CH₂)_(m)—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—P(═O)(R³)₂,—(CH₂)_(m)O—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—(CH₂)_(m) 13 P(═O)(R³)₂,—(CH₂)_(m)—NR¹C(O)O—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—C(O)—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—C(O)NR¹—(CH₂)_(m)—P(═O)(R³)₂ in which m is 0, 1, 2, 3 or 4.

Illustrative examples of this class are the following compounds ofFormula IA:

In certain embodiments, R^(a) contains a —P(═O)(R³)₂ substituent as partof a cyclic structure. For example, two R³ groups can combine to form aring system including a phosphorous atom, wherein the ring system is a5-, 6- or 7-membered saturated ring, optionally substituted; and whichcan optionally contain one heteroatom selected from N, O and S(O)_(r).In certain embodiments, R^(a) is or contains a group described by one ofthe following formulas:

Illustrative examples of this class are compounds of Formula Ia include:

In other cases, R^(a) is a ring system containing the moiety —P(═O)(R³)—as a ring member, such as a 5-, 6- or 7-membered saturated ring,optionally substituted; which contains a phosphorous atom and canoptionally contains 1 heteroatom selected from N, O and S(O)_(r). Incertain embodiments, R^(a) is or contains a group described by one ofthe following formulas:

Illustrative examples of this class are compounds of Formula IA include:

In one subclass of interest, one of R^(a) is —(CH₂)_(m)—P(═O)(R³)₂. Thisclass is illustrated by compounds of Formula II.

in which variables R³, R^(a), n, Ring A, X¹, X², X³ and X⁴ are asdefined above in Formula I and m is 0, 1, 2, 3 or 4.

One class of compounds which is of special interest for use in theinvention are compounds of Formula II, as described above, in which X²is CR^(c), X³ is CR^(d) and X⁴ is CR^(c). This class is illustrated bycompounds of Formula IIA:

in which variables R³, R^(a), Ring A, n, X¹, R^(c), R^(d), and R^(e) areas defined above in Formula I and m is 0, 1, 2, 3 or 4.

In one subclass of interest are compounds of Formula II or IIA in whichm is 0. In another subclass m is 1.

In another subclass of interest are compounds of Formula II or FormulaIIA in which X is N.

In another subclass of interest are compounds of Formula II or FormulaIIA in which X is CR^(b).

In another subclass of interest are compounds of the above classes andsubclasses in which n is 0. In another subclass n is 1.

One class of compounds of special interest are compounds of Formula IIAin which Ring A is a phenyl.

Non limiting examples of this embodiment include the following compoundsof Formula IIA:

In one embodiment, two adjacent substituents selected from R^(c1),R^(d1), R^(c) and R^(d), form with the atoms to which they are attacheda 5-, 6- or 7-membered saturated, partially saturated or unsaturatedRing B, which is substituted with 1 to 4 R^(f); and which contains 0-4heteroatoms selected from N, O and S(O)_(r). This class is illustratedby compounds of Formula III:

in which variables R^(a), R^(f), Ring A, n, s, X¹, X², X³ and X⁴ are asdescribed in Formula I; and t is 1, 2, 3 or 4.

One class of compounds which is of special interest for use in theinvention are compounds of Formula III, as described above, in which X²is CR^(c), X³ is CR^(d) and X⁴ is CR^(e) and R^(c) and R^(d) moietiesform with the atoms to which they are attached a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated Ring B. This class isillustrated by compounds of Formula IIIA:

in which variables R^(a), X¹, Ring A, n, s, t, X¹, R^(e) and R^(f) areas described in Formula III.

In one particular embodiment, one R^(a) is or contains —P(═O)(R³)₂ or aring system containing the moiety —P(═O)(R³)— as a ring member (i.e.(CH₂)_(m)P(═O)(alkyl)₂, in which m is 0, 1, 2, 3 or 4 and other examplesof phosphorous containing substituents, including cyclic ones as listedabove). In another particular embodiment, R^(f) is or contains—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)— as a ringmember (i.e. (CH₂)_(n)P(═O)(alkyl)₂, in which m is 0, 1, 2, 3 or 4 andother examples of phosphorous containing substituents, including cyclicones as listed above).

One class of compounds of special interest are compounds of Formula IIIor IIIA in which Ring A is a phenyl.

Illustrative examples of this class are the following compounds ofFormula IIIA:

Other Illustrative examples of this class are the following compounds ofFormula III:

In another embodiment, two adjacent substituents selected from R^(d1),R^(e1), R^(d) and R^(e) form with the atoms to which they are attached a5-, 6- or 7-membered saturated, partially saturated or unsaturated RingC, which is substituted with 1 to 4 R^(f); and which contains 0-4heteroatoms selected from N, O and S(O)_(r). This class is illustratedby compounds of Formula IV:

in which Ring A, R^(a), R^(f), s, n, X¹, X², X³ and X⁴ are as defined inFormula I; and t is 1, 2, 3 or 4.

Illustrative examples of this class are the following compounds ofFormula IV:

One class of compounds which is of special interest for use in theinvention are compounds of Formula IV, as described above, in which X¹is CR^(b), X² is CR^(c), X³ is CR^(d) and X⁴ is CR^(e) and R^(d) andR^(e) moieties form with the atoms to which they are attached a 5-, 6-or 7-membered saturated, partially saturated or unsaturated Ring C. Thisclass is illustrated by compounds of Formula IVA:

in which Ring A, Ring C, R^(a), s, n, R^(b), R^(c), R^(f) and t are asdefined above in Formula IV.

In one particular aspect of this embodiment, one R^(a) is or contains—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)— as a ringmember.

In another aspect of this embodiment, one of R^(f) is or contains—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)— as a ringmember.

In another aspect of this embodiment, R^(c) is or contains —P(═O)(R³)₂or a ring system containing the moiety —P(═O)(R³)— as a ring member.

One class of compounds of special interest are compounds of Formula IVor IVA in which Ring A is a phenyl.

Illustrative examples of this class are the following compounds ofFormula IVA:

In another embodiment, two adjacent substituents selected from R^(b),R^(c), R^(b1) and R^(c1) form with the atoms to which they are attacheda 5-, 6- or 7-membered saturated, partially saturated or unsaturatedRing D, which is substituted with 1 to 4 R^(f) groups; and whichcontains 0-4 heteroatoms selected from N, O and S(O)_(r). This class isillustrated by compounds of Formula V:

in which R^(a), s, n, X¹, X², X³, X⁴ and R^(f) are as defined above inFormula I; and t is 1, 2, 3 or 4.

Illustrative examples of this class are the following compounds ofFormula V:

One class of compounds which is of special interest for use in theinvention are compounds of Formula V, as described above, in which X¹ isCR^(b), X² is CR^(C), X³ is CR^(d) and X⁴ is CR^(c) and R^(b) and R^(c)form with the atoms to which they are attached a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated Ring D. This class isillustrated by compounds of Formula VA:

in which R^(a), s, n, t, Ring A, Ring D, R^(d), R^(e) and R^(f) are asdefined above in Formula V.

In one particular aspect of this embodiment, one R^(a) is or contains—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)— as a ringmember.

In another aspect of this embodiment, one of R^(f) is or contains—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)— as a ringmember.

One class of compounds of special interest are compounds of Formula V orVA in which Ring A is a phenyl.

Illustrative examples of this class are the following compounds ofFormula VA:

The invention also features compounds of Formula VI:

wherein

X¹ is NR^(b1) or CR^(b);

X³ is NR^(d1) or CR^(d);

X⁴ is NR^(e1) or CR^(e);

Ring A is an aryl, a 5- or a 6-membered heteroaryl ring which contains 1to 4 heteroatoms selected from N, O and S(O)_(r);

Ring E represents an aryl, a carbocyclyl or a 5-, 6- or 7-memberedheterocyclic or heteroaryl ring comprising carbon atoms and 1-4heteroatoms independently selected from O, N and S(O)_(r); Ring E isoptionally fused with a 5-, 6- or 7-membered saturated, partiallysaturated or unsaturated ring and Ring E is substituted on carbon or onthe heteroatom(s) with 1-7 R^(g) groups.

L is a bond, O(CH₂)_(y), NR⁴(CH₂)_(y), S(O)_(r)(CH₂)_(y), (CH₂)_(y),(CH₂)_(y)SO₂NR⁴, (CH₂)_(y)NR⁴SO₂, (CH₂)_(y)CH═CH, (CH₂)_(y)C≡C,

(CH₂)_(y)C(O)NR⁴, (CH₂)_(y)NR⁴C(O); y is 0, 1, 2,3 or 4; p is 1, 2, 3,4, 5, 6 or 7; r is 0, 1 or 2, R⁴ is H or alkyl; and the linker L can beincluded in either direction.

at each occurrence R^(a), R^(b), R^(d), and R^(e) are independentlyselected from the group consisting of halo, —CN, —NO₂, —R¹, —OR²,—O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃,

—NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R², and R^(b1), R^(d1)and R^(e1) are absent; wherein each Y is independently a bond, —O—, —S—or —NR¹—; or

alternatively two adjacent substituents selected from R^(b), R^(b1),R^(d), R^(d1), R^(e) and R^(e1); or two adjacent R^(a) moieties, canform with the atoms to which they are attached a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which contains 0-4heteroatoms selected from N, O and S(O)_(r) and which is substitutedwith one to four R^(f) moities wherein;

each R^(f) moiety is independently selected from the group consisting ofhalo, ═O, =S, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R²,—NR¹—OR², —C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR²,—OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR²,—YP(═O)(YR³)(YR³), —Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and—NR¹SO₂NR¹R²; or alternatively two adjacent R^(f) moieties can form withthe atoms to which they are attached a 5-, 6- or 7-membered saturated,partially saturated or unsaturated ring, optionally substituted; andwhich contains 0-4 heteroatoms selected from N, O and S(O)_(r);

each R^(g) moiety is independently selected from the group consisting ofhalo, ═O, =S, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R²,—NR¹—OR², —C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR²,—OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR²,—YP(═O)(YR³)(YR³), —Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and—NR¹SO₂NR¹R²; wherein each Y is independently a bond, —O—, —S— or —NR¹—;and at least one of R^(a), R^(b), R^(d), R^(e) or R^(g), when present,is or contains —P(═O)(R³)₂ or a ring system containing the moiety—P(═O)(R³)— as a ring member;

r is 0, 1 or 2;

s is 1, 2, 3, 4 or 5

n is 0 or 1;

p is 1, 2, 3 or 4;

each occurrence of Y is independently a bond, —O—, —S— or —NR¹—;

each occurrence of R¹ and R² is independently selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl;

each occurrence of R³ is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic and heteroaryl, or two adjacent R³ moieties combine to forma ring system including a phosphorous atom;

each occurrence of R^(3a) is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic, and heteroaryl;

alternatively, each NR¹R² moiety may be a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which can beoptionally substituted and which contains 0-2 additional heteroatomsselected from N, O and S(O)_(r); and

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl and heterocyclic moiety is optionallysubstituted.

In one embodiment are compounds of Formula VI in which one of R^(a) isor contains —P(═O)(R³)₂.

In another embodiment are compounds of Formula VI in which one of R^(g)is or contains —P(═O)(R³)₂.

In one embodiment are compounds of formula VI in which L is a bond.Non-limiting examples of this class include the following compounds:

In another embodiment are compounds of formula VI in which L isNR⁴(CH₂)_(y). In a particular aspect, L is NR⁴. In another particularaspect, L is NR⁴(CH₂)₁₋₃. Non-limiting examples of L linker areNHCH₂CH₂, NHCH₂, NH and NCH₃. Non limiting examples of this classinclude the following compounds:

In another embodiment are compounds of formula VI in which L isO(CH₂)_(y). Non limiting examples of this class include the followingcompounds:

In another embodiment are compounds of Formula VI in which L is(CH₂)_(y)C(O)NR⁴ or (CH₂)_(y)NR⁴C(O). Non limiting examples of thisclass include the following compounds:

In another embodiment are compounds of formula VI in which L isS(CH₂)_(y). Non limiting examples of this class include the followingcompounds:

In still another embodiment are compounds of Formula VI in which Ring Eis an aryl, substituted with 1 to 5 R^(g) groups. Non-limiting examplesof this class are compounds of the following types:

In another embodiment are compounds of Formula VI in which Ring E is a5-, 6- or 7-membered heterocyclyl ring comprising carbon atoms and 1-3heteroatoms independently selected from O, N and S(O)_(r), and Ring E issubstituted on carbon or on the heteroatom(s) with 1-7 R^(g) groups. Itis understood that the total number of substituents R^(g) does notexceed the normal available valencies. Non-limiting examples of thisclass are compounds of formula VI in which Ring E is of the followingtypes:

Non-limiting illustrative examples are compounds of the followingformulae:

In another embodiment are compounds of Formula VI in which Ring E is acarbocyclyl ring and Ring E is substituted with 1-7 R^(g) groups.Non-limiting examples of this class are compounds of the followingtypes:

In another aspect of the previous embodiment, Ring E is a 5-, 6- or7-membered heteroaryl ring comprising carbon atoms and 1-3 heteroatomsindependently selected from O, N and S(O)_(r). For example, Ring E canbe a 5-membered ring heteroaryl comprising carbon atoms and 1-3 Nitrogenatoms. Non-limiting examples of this class are compounds in which Ring Eis of the following types:

In certain embodiments, Ring E has the following formulae:

Of additional interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹ and —C(O)YR².In another subclass of interest, are compounds of the above embodimentin which R^(g) is an aryl, heteroaryl, substituted alkyl orheterocyclyl. Non limiting examples of substituted alkyl are—(CH₂)_(z)C(═O)NR¹R², —(CH₂)_(z)NHC(═O)R², —(CH₂)_(z)NR¹R²,—(CH₂)_(z)C(═O)OR¹, —(CH₂)_(z)heterocyclyl, —(CH₂)_(z)aryl,—(CH₂)_(z)heteroaryl in which z is 1, 2, 3 or 4 and alkyl includestraight (i.e. unbranched or acyclic), branched and cyclic alkyl groupsand alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Illustrative examples of such Ring E groups including substituent R^(g)include, without limitation:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another embodiment, Ring E is a 5-membered ring heteroaryl comprisingcarbon atoms and 1-3 Nitrogen atoms and the heteroaryl ring is linked tothe core moiety via a nitrogen atom. In one preferred aspect of thisembodiment L is a bond or (CH₂)_(y).

Of additional interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹, —OR²,—P(═O)(R³)₂, —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R²,—SO₂NR¹R² and —NR¹SO₂NR¹R². In another subclass of interest, arecompounds of the above embodiment in which R^(g) is an aryl, heteroaryl,substituted alkyl or heterocyclyl. Non limiting examples of R^(g) are—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl and NH-heterocyclyl; in which y is 0, 1, 2, 3 or 4 andalkyl include straight (i.e. unbranched or acyclic), branched and cyclicalkyl groups and alkyl, aryl, heteroaryl, heterocyclyl groups areoptionally substituted.

Illustrative non limiting examples of such compounds include compoundsof Formula VI in which Ring E is a triazole of the following formulae:

In another embodiment, Ring E is a pyrazole of the following formulae:

In another aspect of the previous embodiment, Ring E is a tetrazole ofthe following formulae:

In another embodiment, Ring E is a 5-membered ring heteroaryl comprisingcarbon atoms and 1-3 heteroatoms selected from N and O. Non limitingexamples are compounds of formula VI in which Ring E is of the followingtype:

in which p is defined previously and the total number of substituentsR^(g) does not exceed the normal available valencies.

In certain particular embodiments, Ring E has the following formulae:

in which Ring E is substituted with one or two R^(g) substituents.

Of additional interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹, —P(═O)(R³)₂,—OR², —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R²and —NR¹SO₂NR¹R². In another subclass of interest, are compounds of theabove embodiment in which R^(g) is NHC(O)R¹, NHC(O)NR¹R², C(O)NHR¹,C(O)NR¹R², NR¹R², an aryl, heteroaryl, substituted alkyl orheterocyclyl. Non limiting examples of R^(g) are —(CH₂)_(y)C(═O)NR¹R²,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl and NH-heterocyclyl, —(CH₂)_(m)P(═O)(alkyl)₂; in which yand m are independently selected from 0, 1, 2, 3 and 4 and alkyl includestraight (i.e. unbranched or acyclic), branched and cyclic alkyl groupsand alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Non-limiting examples of this class include compounds of formula VI inwhich Ring E is:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In another specific embodiment, Ring E is a 5-membered heteroarylcomprising carbon atoms and 1-3 heteroatoms selected from N and S.

in which p is defined previously and the total number of substituentsR^(g) does not exceed the normal available valencies.

Of particular interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹, —P(═O)(R³)₂,—OR², —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R²and —NR¹SO₂NR¹R². In another subclass of interest, are compounds of theabove embodiment in which R^(g) is NHC(O)R¹, C(O)NHR¹, C(O)NR¹R²,NHC(O)NHR¹, NR¹R², an aryl, heteroaryl, substituted alkyl orheterocyclyl. Non limiting examples of R^(g) are —(CH₂)_(y)C(═O)NR¹R²,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —SO₂NR¹R²,—(CH₂)_(y)SR² , —(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl,—(CH₂)_(y)heteroaryl, —NH-aryl, —NH-heteroaryl, NH-heterocyclyl and—(CH₂)_(m)P(═O)(alkyl)₂; in which y and m are indenpendently selectedfrom 0, 1, 2, 3 and 4 and alkyl include straight (i.e. unbranched oracyclic), branched and cyclic alkyl groups and alkyl, aryl, heteroaryl,heterocyclyl groups are optionally substituted.

Non-limiting examples of this class include compounds of formula VI inwhich Ring E is:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

Other non-limiting examples include compounds of formula VI in whichRing E is furan or thiofuran:

in which p is defined previously and the total number of substituentsR^(g) does not exceed the normal available valencies.

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In another embodiment, Ring E is a 6-membered heteroaryl ring. Forexample, Ring E can be a pyrimidine of the following types:

in which p is as previously described and the total number ofsubstituents R^(g) does not exceed the normal available valencies.

Of particular interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹, —P(═O)(R³)₂,—OR², —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R²and —NR¹SO₂NR¹R². In another subclass of interest, are compounds of theabove embodiment in which R^(g) is NHC(O)R¹, NHC(O)NHR¹, C(O)NHR¹,C(O)NR¹R², NR¹R², an aryl, heteroaryl, substituted alkyl orheterocyclyl. Non limiting examples of R^(a) are —OCH₂CH₂NR¹R²,—OCH₂C(O)NR¹R², —NR¹C(O)NR¹R², —(CH₂)_(y)C(═O)NR¹R²,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —SO₂NR¹R²,—(CH₂)_(y)SR², —(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl,—(CH₂)_(y)heteroaryl, NH-aryl, NH-heteroaryl, NH-heterocyclyl and—(CH₂)_(m)P(═O)(alkyl)₂; in which y and m are independently selectedfrom 0, 1, 2, 3 and 4 and alkyl include straight (i.e. unbranched oracyclic), branched and cyclic alkyl groups and alkyl, aryl, heteroaryl,heterocyclyl groups are optionally substituted.

Non-limiting examples of this class are compounds of formula VI in whichRing E is:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In another embodiment, Ring E is a pyridine substituted with 1-4 R^(g).Of particular interest is a class of compounds as described above inwhich R^(g) is selected from the group consisting of —R¹, —P(═O)(R³)₂,—OR², —NR¹R², —NR¹C(O)R², —NR¹SO₂R². In another subclass of interest,are compounds of the above embodiment in which R^(g) is NHC(O)R², NR¹R⁴,an aryl, heteroaryl, substituted alkyl or heterocyclyl. Non limitingexamples of R^(g) are —(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)C(═O)aryl,—(CH₂)_(y)C(═O)beteroaryl, —(CH₂)_(y)C(═O)heterocyclyl,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —(CH₂)_(y)SR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, —NH-aryl,NH-heteroaryl, NH-heterocyclyl and —(CH₂)_(m)P(═O)(alkyl)₂; in which yand m are independently selected from 0, 1, 2, 3 and 4; and alkylinclude straight (i.e. unbranched or acyclic), branched and cyclic alkylgroups and alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Non-limiting examples of this class are compounds of formula VI in whichRing E is:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In another embodiment, Ring E is a pyrazine substituted with 1-3 R^(g)groups. Non-limiting examples of this class of compounds in which Ring Eis:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In another embodiment, Ring E is a triazine substituted with 1 to 2R^(g) groups. Examples include compounds in which Ring E has thefollowing formulae:

in which p is defined previously and the number of substituents R^(g)does not exceed the maximum available valencies, which in the triazinecase p is 0, 1 or 2.

In one embodiment, Ring E is an aryl, a carbocyclyl or a 5-, 6- or7-membered heterocyclic or heteroaryl ring which is fused with a 5- or6- or 7-membered saturated, partially saturated or unsaturated ring, andRing E is optionally substituted with 1-5 R^(g) groups.

In certain embodiments, Ring E is a 5,6- or 5,5-bicyclic fused system.Non-limiting examples include compounds of formula VI in which Ring Ehas the following formulae:

and the depicted fused ring systems can be substituted with additionalR^(g) groups.

In some other embodiments of interest, Ring E is a 6,6- or 6,5-bicyclicfused system. Non limiting examples of this class include compounds offormula VI in which Ring E has the following formulae:

and the depicted fused ring systems can be substituted with additionalR^(g) groups.

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In some other embodiments of interest, Ring E is an aryl fused with a5-, 6-or 7-membered saturated, partially saturated or unsaturated ring,and Ring E is substituted with 1-5 R^(g) groups.

Non limiting examples of this class include compounds of formula VI inwhich Ring E has the following formulae:

Specific, non-limiting illustrative examples of this class includecompounds of formula VI in which substituted Ring E is of the followingformulae:

In embodiments of the compounds of formula VI, Ring A is a 6-memberedring heteroaryl. Examples of this class are compounds of the aboveclasses and subclasses in which Ring A is a pyridine, pyrazine,pyridazine, pyrimidine or triazine.

In still other embodiments, Ring A is a 5-membered ring heteroaryl.Examples of this class are compounds of the above classes and subclassesin which Ring A is imidazole, pyrazole, tetrazole, oxazole, thiazole,isoxazole, pyrrole, and the like.

Of particular interest is a class of compounds as described above inwhich R^(a) is selected from the group consisting of halo, —P═O(R³)₂,—R¹, —OR², —NR¹R², —NR¹C(O)R², —NR¹C(O)NR², —C(O)NR¹R², C(O)OR¹,—SO₂NR¹R², —SO₂R¹, —NR¹SO₂R². In another subclass of interest, arecompounds of the above embodiment in which R^(a) is —P(═O)(alkyl)₂,alkyl, alkynyl, halo, aryl, heteroaryl, heterocyclyl, O-alkyl (i.e: OMeand the like), —CN, —C(O)NH-alkyl, —C(O)NH-aryl, C(O)NH-heterocyclyl,OH, —NR¹R², NHS(O)₂-alkyl, NHS(O)₂-aryl. Non limiting examples of R^(a)are is —(CH₂)_(m)P(═O)(Me)₂, —(CH₂)_(m)P(═O)(Et)₂, F, Cl, CF₃, OCF₃,—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)C(═O)aryl, —SO₂NR¹R², NHSO₂R¹, loweralkyl, —(CH₂)_(y)C(═O)heteroaryl, —(CH₂)_(y)C(═O)heterocyclyl,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —(CH₂)_(y)SR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl, NH-heterocyclyl, in which y and m are independentlyselected from 0, 1, 2, 3 and 4; and alkyl include straight (i.e.unbranched or acyclic), branched and cyclic alkyl groups and alkyl,aryl, heteroaryl, heterocyclyl groups are optionally substituted.

The invention also features compounds of Formula VIa:

wherein

X¹ is NR^(b1) or CR^(b);

X³ is NR^(d1) or CR^(d);

X⁴ is NR^(e1) or CR^(e);

Ring A and Ring E are each an independently selected aryl or heteroarylring, the heteroaryl ring being a 5- or 6-membered ring containing 1 to4 heteroatoms selected from N, O and S(O)_(r);

each occurrence of R^(a), R^(b), R^(d), R^(e), and R^(g) isindependently selected from the group consisting of halo, 13 CN, —NO₂,—R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R²; oralternatively, each R^(a) and R^(g) may also be or include anindependently selected moiety, —P(═O)(R³)₂ or a ring system containingthe moiety —P(═O)(R³)— as a ring member;

R^(b1), R^(d1) and R^(e1) are absent;

or alternatively two adjacent substituents selected from R^(d), R^(d1),R^(e), and R^(e1) or two adjacent R^(a) moieties, can form, with theatoms to which they are attached, a fused, 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which contains 0-4heteroatoms selected from N, O and S(O)_(r) and which may bear up tofour substituents suitable for heterocycles (see infra), a variety ofwhich are illustrated in exemplary compounds disclosed herein;

at least one of R^(a) and R^(g) is or contains a moiety, —P(═O)(R³)₂ ora ring system containing the moiety —P(═O)(R³)— as a ring member;

L is O or NH;

r is 0, 1 or 2;

s is 1, 2, 3, 4 or 5;

p is 1, 2, 3 or 4;

each occurrence of Y is independently a bond, —O—, —S— or —NR¹—;

each occurrence of R¹ and R² is independently H or an alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic or heteroaryl moiety;

each occurrence of R³ is independently an alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclicor heteroaryl moiety, or two adjacent R³ moieties combine to form a ringsystem including a phosphorous atom;

each occurrence of R^(3a) is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic, and heteroaryl;

alternatively, each NR¹R² moiety may be a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which can beoptionally substituted and which contains 0-2 additional heteroatomsselected from N, O and S(O)_(r); and

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl and heterocyclic moieties is optionallysubstituted.

In certain embodiments of the compounds of Formula VIA are furtherdefined as follows (1) X¹ is N; (2) X³ is N and X⁴ is CR^(e); (3) X³ isCR^(d) and X⁴ is CR^(e); (4) X¹ is CR^(b); (5) X³ is N and X⁴ is CR^(e);or (6) X³ is CR^(d) and X⁴ is CR^(e).

In certain specific embodiments of the compounds of Formula VIA, when X³is CR^(d), R^(d) is selected from Cl, F, C1-C4 alkyl, trihaloalkyl,cycloalkyl, C2-C4 alkenyl, and alkynyl. In such embodiments, Cl, F, Meand cyclopropyl are of particular interest.

In another embodiment of the compounds of Formula VIA, X³ is CR^(d) andX⁴ is CR^(e) wherein R^(d) and R^(e), together with the atoms to whichthey are attached, form a fused, 5-, 6- or 7-membered saturated,partially saturated or unsaturated ring, which contains 0-4 heteroatomsselected from N, O and S(O)_(r) and which may bear up to foursubstituents.

Compounds of Formula VIA of particular interest, generally and includingthe individual embodiments described above, include those in which s is1, 2, 3 or 4, and each of the substituents R^(a) is independentlyselected from halo, —R¹, —OR², —NR¹R² and —P(═O)(R³)₂, wherein each R¹and R² moiety may be further substituted or unsubstituted. In certainembodiments, the compounds include at least one substituent R^(a) thatis —OR² and R² is selected from C1-C6 alkyl, C2-C6, and C2-C6 alkynyl.In such cases, as illustrated in compounds shown herein, MeO—, EtO— andiPrO— are often chosen as an R^(a) moiety.

Compounds of Formula VIA, generally and including the individualembodiments described thus far, also include compounds having at leastone substituent R^(a) which is a 4-, 5-, 6- or 7-membered heterocyclicor 5- or 6-membered heteroaryl moiety, linked to Ring A either directlyor by an ether bond, and which may be further substituted with 1-3substituents independently selected from halo, 13 CN, —NO₂, —R¹, —OR²,—O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R²;wherein each Y is independently a bond, —O—, —S— or —NR¹—.

For example, compounds of Formula VIA include those having aheterocyclic or heteroaryl substituent R^(a) is selected from thefollowing:

Compounds of Formula VIA, generally and, again, including the individualembodiments described thus far, also include compounds of Formula VIA inwhich at least one substituent R^(a) is or bears a moiety, —P(═O)(R³)₂,in which R³ is a C1-C4 alkyl.

Compounds of Formula VIA, generally and, again, including theembodiments described thus far, also include embodiments of Formula VIAin which L is NH, Ring E is aryl, and each R^(g) is independentlyselected from halo, —R¹, —OR², —S(O)_(r)R² and —P(═O)(R³)₂. In certainembodiments, Ring E contains at least one such R^(g) moiety in the orthoposition relative to the ring atom attached to L. In other embodiments,that R^(g) moiety is in the meta position relative to the ring atomattached to L, and in still other embodiments, that R^(g) moiety is inthe para position relative to the ring atom attached to L.

Embodiment of the compounds of formulas VI and VIA, generally and,again, including the individual embodiments described thus far, alsoinclude those compounds in which the group —P(═O)(R³)₂ is selected from—P(═O)(CH₃)₂ and —P(═O)(CH₂CH₃)₂.

In another embodiment of compounds of Formula I, two adjacent R^(a) forma 5-, 6- or 7-membered saturated, partially saturated or unsaturatedRing F which is substituted with 1-4 R^(f) groups. This class ofcompounds is represented by compounds of formula VII:

in which Ring A, R^(a), R^(f), n, X¹, X², X³ and X⁴ are as defined inFormula I; t is 1, 2, 3 or 4; and Ring F is an aryl, a carbocyclyl, a 5-or 6-or 7-membered heteroaryl or heterocyclyl ring substituted with 1-4R^(f) groups.

One class of compounds which is of special interest for use in theinvention are compounds of Formula VII are those in which X² is CR^(c),X³ is CR^(d) and X⁴ is CR^(e). This class is illustrated by compounds offormula VIIA:

in which Ring A, Ring F, R^(a), R^(f), t, n, X¹, R^(c), R^(d) and R^(e)are as defined previously in Formula VII.

One class of compounds of further interest are compounds of Formula VIIAin which Ring A is a phenyl. This is represented by compounds of FormulaVIIB:

in which Ring F, R^(a), R^(f), t, n, X¹, R^(c), R^(d) and R^(e) are asdescribed in Formula VII.

In Formulas VII, VIIA, and VIIB, Ring A and Ring F together form a fusedring system. Fused ring systems that can be utilized in compounds offormulas VII, VIIA, and VIIB include, without limitation, those depictedfor Ring E of Formula VI (see below) and the following fused ringsystems:

The fused ring systems are optionally substituted with additional R^(a)or R^(f) groups. Of special interest are compounds of formula VII orVIIA or VIIB in which R^(f) is or contains —P(═O)(R³)₂. Examples ofR^(f) containing —P(═O)(R³)₂ include, without limitation,—(CH₂)_(m)—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—P(═O)(R³)₂,—(CH₂)_(m)—O—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—NR¹C(O)O—(CH₂)_(m)—P(═NR³)₂, and—(CH₂)_(m)—C(O)NR¹—(CH₂)_(m)—P(═O)(R³)₂, in which m is 0, 1, 2, 3 or 4and ring systems containing the moiety —P(═O)(R3)— as a ring member.

Of other special interest are compounds of Formula VII or VIIA or VIIBin which R^(e) is or contains —P(═O)(R³)₂.

In one embodiment of any of the above classes and subclasses ofcompounds, Ring A is a phenyl group substituted with 1-5 R^(a) moieties.In certain embodiments of any of the above classes and subclasses ofcompounds, Ring A is a 6-membered ring heteroaryl (eg., a pyridine,pyrazine, pyridazine, pyrimidine or triazine ring). In still otherembodiments of any of the above classes and subclasses of compounds,Ring A is a 5-membered ring heteroaryl (e.g., an imidazole, pyrazole,tetrazole, oxazole, thiazole, isoxazole, or pyrrole ring).

In another embodiment of any of the above classes and subclasses ofcompounds, R^(a) is selected from halo, —P═O(R³)₂, —R¹, —OR², —NR¹R²,—NR¹C(O)R², —NR¹C(O)NR², —C(O)NR¹R², —C(O)OR¹, —SO₂NR¹R², —SO₂R¹, and—NR¹SO₂R².

Another subclass of interest are compounds of the above embodiment inwhich R^(a) is —P(═O)(alkyl)₂, alkyl, alkynyl, halo, aryl, heteroaryl,heterocyclyl, —O-alkyl (i.e: OMe and the like), —CN, —C(O)NH-alkyl,—C(O)NH-aryl, —C(O)NH-heterocyclyl, —OH, —NR¹R², NHS(O)₂-alkyl,—NHS(O)₂-aryl. Non limiting examples of R^(a) include—(CH₂)_(m)P(═O)(Me)₂, —(CH₂)_(m)P(═O)(Et)₂, —F, —Cl, —CF₃, —OCF₃,—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)C(═O)aryl, —SO₂NR¹R², —NHSO₂R¹, loweralkyl, —(CH₂)_(y)C(═O)heteroaryl, —(CH₂)_(y)C(═O)heterocyclyl,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —(CH₂)_(y)SR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, —NH-aryl,—NH-heteroaryl, —NH-heterocyclyl, wherein y and m are independentlyselected from 0, 1, 2, 3 and 4.

In still another embodiment of any of the above classes and subclassesof compounds, R^(a) is selected from —P(═O)(alkyl)₂,—(CH₂)₁₋₂P(═O)(alkyl)₂, —O-lower alkyl (i.e OMe and the like), loweralkyl (i.e: methyl, ethyl, cyclopropyl and the like), halo, —CF₃, —OCF₃,—CN, —NH(alkyl), alkenyl, and alkynyl (i.e: acetylene).

Illustrative examples of Phenyl moieties substituted with R^(a) include,without limitation, the following moieties:

In any of the above classes and subclasses of compounds, R^(a) isselected from —(CH₂)_(m)—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—P(═O)(R³)₂,—(CH₂)_(m)—O—P(═O)(R³)₂, —(CH₂)_(m)—NR¹—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—NR¹C(O)O—(CH₂)_(m)—P(═O)(R³)₂, and—(CH₂)_(m)—C(O)NR¹—(CH₂)_(m)—P(═O)(R³)₂, in which m is 0, 1, 2, 3 or 4.Alternatively, R^(a) is a moiety of one of the following formulas:

For these classes and other classes and subclasses of the invention,compounds of interest include among others compounds in which one ofR^(a) is or contains —P(═O)(R³)₂. Examples of R^(a) containing—P(═O)(R³)₂ include, without limitation, —(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—NR¹—P(═O)(R³)₂, —(CH₂)_(m)—O—P(═O)(R³)₂,—(CH₂)_(m)—NR¹—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—NR¹C(O)O—(CH₂)_(m)—P(═O)(R³)₂,—(CH₂)_(m)—C(O)NR¹—(CH₂)_(m)—P(═O)(R³)₂ in which m is 0, 1, 2, 3 or 4and cyclic structures containing —P(═O) as depicted above. Of particularcurrent interest are compounds of Formula Ia or VIa in which Ring A isphenyl, X¹ is N, n is 0, s is 2, p is 1, R^(e) is H and R^(d) is halo(i.e, F, Cl), lower alkyl (i.e. methyl, ethyl, isopropyl and the like),cyano, nitro, alkoxy (i.e. methoxy and the like) or CF₃; one of R^(a) isor contains —P(═O)(R³)₂ and the other R^(a) is selected from loweralkyl, halo, cyano and alkoxy (i.e. methoxy); and R^(g) is S(O)₂alkyl.

Of other special interest for use in the invention are compounds offormula IIIA in which Ring A is phenyl. Illustrative, non-limitingexamples of this subclass are compounds of the formulae:

Of special interest for use in the invention are compounds of formulaIIIA in which one of R^(a) is or contains —P(═O)(R³)₂ (i.e CH₂P(═O)Me₂,—P(═O)Me₂, —P(═O)Et₂, —OP(═O)Me₂, —NHP(═O)Me₂, —NHCH₂P(═O)Et₂ and thelike). Of particular current interest are compounds of this subclass inwhich X¹ is N, n is 0, R^(e) is H and R^(f) is selected from alkyl, H,aryl, heteroaryl, heterocyclyl, halo (i.e, F, Cl), NHR¹, OR₂, CF₃,SO₂-lower alkyl (i.e. SO₂-iPr and the like), —SO₂NR¹R² and C(O)NR¹R².

Other compounds of interest include among others, compounds of formulaIIIA in which R^(f) is —(CH₂)_(m)P(═O)(alkyl)₂ (i.e —CH₂P(═O)Me₂,—P(═O)Me₂, —P(═O)Et₂, etc.). Of particular current interest arecompounds of this subclass in which X¹ is N, n is 0, R^(a) is methoxy,and R^(e) is H.

Other compounds of interest include among others, compounds of theprevious classes and subclasses in which R^(d) is selected from H, halo(i.e Chloro, Fluoro, Bromo), —CF₃, optionally substituted lower alkylgroup (i.e Methyl, Ethyl, Isopropyl, Cyclopropyl and the like), —CN,optionally substituted acetylene, —NO₂, —O-alkyl, —S-alkyl, —C(═O)alkyl,—NH-alkyl and —C(═O)N(alkyl)₂. Of further interest are compounds of thisclass in which R^(d) is halo or CF³.

Other compounds of interest include among others, compounds of theFormula I and IA and of all previous classes and subclasses in whichR^(e) is selected from halo, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —C(O)YR²,—OC(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR²,—YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR². Of further interest are compounds ofthis class in which R^(e) is H, CN, NO₂, lower alkyl or halo, whereinR¹, R², and Y are as defined in Formula I. Of further interest, R^(e) isselected from H, lower alkyl and halo.

Compounds of the invention of particular interest include those with onor more of the following characteristics:

a molecular weight of less than 1000, preferably less than 750 and morepreferably less than 600 mass units (not including the weight of anysolvating or co-crystallizing species, of any counter-ion in the case ofa salt); or

inhibitory activity against a wild type or mutant (especially aclinically relevant mutant) kinase, especially a kinase such as ALK,Met, Jak2 , bRaf, EGFR, Tie-2, FLT3 or another kinase of interest withan IC₅₀ value of 1 μM or less (as determined using any scientificallyacceptable kinase inhibition assay), preferably with an IC₅₀ of 500 nMor better, and optimally with an IC₅₀ value of 250 nM or better; or

inhibitory activity against a given kinase with an IC50 value at least100-fold lower than their IC₅₀ values for other kinases of interest; or

inhibitory activity for ALK, Met, Jak2 or B-Raf with a 1 μM or betterIC₅₀ value against each; or

a cytotoxic or growth inhibitory effect on cancer cell lines maintainedin vitro, or in animal studies using a scientifically acceptable cancercell xenograft model, (especially preferred are compounds of theinvention which inhibit proliferation of Ba/F3 NMP-ALK, Ba/F3 EML4-ALK,Karpas 299 and/or SU-DHL-1 cells with a potency at least as great as thepotency of known ALK inhibitors such as NVP-TAE684 and PF2341066 amongothers, preferably with a potency at least twice that of known ALKinhibitors, and more preferably with a potency at least 10 times that ofknown ALK inhibitors as determined by comparative studies.

Also provided is a composition comprising at least one compound of theinvention or a salt, hydrate or other solvate thereof, and at least onepharmaceutically acceptable excipient or additive. Such compositions canbe administered to a subject in need thereof to inhibit the growth,development and/or metastasis of cancers, including solid tumors (e.g.,prostate cancer, colon cancer, pancreatic and ovarian cancers, breastcancer, non small cell lung cancer (NSCLS), neural tumors such asglioblastomas and neuroblastomas; esophaegeal carcinomas, soft tissuecancers such as rhabdomyosarcomas; among others); various forms oflymphoma such as a non-Hodgkin's lymphoma (NHL) known as anaplasticlarge-cell lymphoma (ALCL), various forms of leukemia; and includingcancers which are resistant to other treatment, including those whichare resistant to treatment with another kinase inhibitor, and generallyfor the treatment and prophylaxis of diseases or undesirable conditionsmediated by one or more kinases which are inhibited by a compound of theinvention.

The invention features a method for treating cancer. The method includesadministering (as a monotherapy or in combination with one or more otheranti-cancer agents, one or more agents for ameliorating side effects,radiation, etc) a therapeutically effective amount of a compound of theinvention to a human or animal in need of it in order to inhibit, slowor reverse the growth, development or spread of cancer, including solidtumors or other forms of cancer such as leukemias, in the recipient.Such administration constitutes a method for the treatment orprophylaxis of diseases mediated by one or more kinases inhibited by oneof the disclosed compounds or a pharmaceutically acceptable derivativethereof. “Administration” of a compound of the invention encompasses thedelivery to a recipient of a compound of the sort described herein, or aprodrug or other pharmaceutically acceptable derivative thereof, usingany suitable formulation or route of administration, as discussedherein. Typically the compound is administered one or more times permonth, often one or more times per week, e.g. daily, every other day, 5days/week, etc. Oral and intravenous administrations are of particularcurrent interest.

The phrase, “pharmaceutically acceptable derivative”, as used herein,denotes any pharmaceutically acceptable salt, ester, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite(MW>300) thereof which is pharmacologically active as a kinaseinhibitor. Pharmaceutically acceptable derivatives thus include amongothers pro-drugs. A pro-drug is a derivative of a compound, usually withsignificantly reduced pharmacological activity, which contains anadditional moiety which is susceptible to removal in vivo yielding theparent molecule as the pharmacologically active species. An example of apro-drug is an ester which is cleaved in vivo to yield a compound ofinterest. Pro-drugs of a variety of compounds, and materials and methodsfor derivatizing the parent compounds to create the pro-drugs, are knownand may be adapted to the invention.

Particularly favored derivatives and prodrugs of a parent compound arethose derivatives and prodrugs that increase the bioavailability of thecompound when administered to a mammal (e.g., by permitting enhancedabsorption into the blood following oral administration) or whichenhance delivery to a biological compartment of interest (e.g., thebrain or lymphatic system) relative to the parent compound. Preferredprodrugs include derivatives of a compound of the invention withenhanced aqueous solubility or active transport through the gutmembrane, relative to the parent compound.

One important aspect of the invention is a method for treating cancer ina subject in need thereof, which comprises administering to the subjecta treatment effective amount of a composition containing a compound ofthe invention. Treatment may be provided in combination with one or moreother cancer therapies, include surgery, radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes, etc.),endocrine therapy, biologic response modifiers (e.g., interferons,interleukins, and tumor necrosis factor (TNF) to name a few),hyperthermia, cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other cancer chemotherapeutic drugs. The otheragent(s) may be administered using a formulation, route ofadministration and dosing schedule the same or different from that usedwith the compound of the invention.

Such other drugs include but not limited to one or more of thefollowing: an anti-cancer alkylating or intercalating agent (e.g.,mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, andIfosfamide); antimetabolite (e.g., Methotrexate); purine antagonist orpyrimidine antagonist (e.g., 6-Mercaptopurine, 5-Fluorouracil,Cytarabile, and Gemcitabine); spindle poison (e.g., Vinblastine,Vincristine, Vinorelbine and Paclitaxel); podophyllotoxin (e.g.,Etoposide, Irinotecan, Topotecan); antibiotic (e.g., Doxorubicin,Bleomycin and Mitomycin); nitrosourea (e.g., Carmustine, Lomustine);inorganic ion (e.g., Cisplatin, Carboplatin, Oxaliplatin or oxiplatin);enzyme (e.g., Asparaginase); hormone (e.g., Tamoxifen, Leuprolide,Flutamide and Megestrol); mTOR inhibitor (e.g., Sirolimus (rapamycin),Temsirolimus (CCI779), Everolimus (RAD001), AP23573 or other compoundsdisclosed in US Patent No. 7,091,213); proteasome inhibitor (such asVelcade, another proteasome inhibitor (see e.g., WO 02/096933) oranother NF-kB inhibitor, including, e.g., an IkK inhibitor); otherkinase inhibitors (e.g., an inhibitor of Src, BRC/Abl, kdr, flt3,aurora-2, glycogen synthase kinase 3 (“GSK-3”), EGF-R kinase (e.g.,Iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R kinase, etc); an antibody,soluble receptor or other receptor antagonist against a receptor orhormone implicated in a cancer (including receptors such as EGFR, ErbB2,VEGFR, PDGFR, and IGF-R; and agents such as Herceptin, Avastin, Erbitux,etc.); etc. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference. Examples of other therapeutic agentsare noted elsewhere herein and include among others, Zyloprim,alemtuzmab, altretamine, amifostine, nastrozole, antibodies againstprostate-specific membrane antigen (such as MLN-591, MLN591RL andMLN2704), arsenic trioxide, bexarotene, bleomycin, busulfan,capecitabine, Gliadel Wafer, celecoxib, chlorambucil,cisplatin-epinephrine gel, cladribine, cytarabine liposomal,daunorubicin liposomal, daunorubicin, daunomycin, dexrazoxane,docetaxel, doxorubicin, Elliott's B Solution, epirubicin, estramustine,etoposide phosphate, etoposide, exemestane, fludarabine, 5-FU,fulvestrant, gemcitabine, gemtuzumab-ozogamicin, goserelin acetate,hydroxyurea, idarubicin, idarubicin, Idamycin, ifosfamide, imatinibmesylate, irinotecan (or other topoisomerase inhibitor, includingantibodies such as MLN576 (XR11576)), letrozole, leucovorin, leucovorinlevamisole,liposomal daunorubicin, melphalan, L-PAM, mesna,methotrexate, methoxsalen, mitomycin C, mitoxantrone, MLN518 or MLN608(or other inhibitors of the flt-3 receptor tyrosine kinase, PDFG-R orc-kit), itoxantrone, paclitaxel, Pegademase, pentostatin, porfimersodium, Rituximab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide,VM-26, topotecan, toremifene, 2C4 (or other antibody which interfereswith HER2-mediated signaling), tretinoin, ATRA, valrubicin, vinorelbine,or pamidronate, zoledronate or another bisphosphonate.

The invention further comprises the preparation of a compound of any ofFormulae I, Ia, II, IIa, III, IIIc, IV, IVa, V, Va, VI, VIa VII, VIIaand VIIb or of any other of compounds of the invention using a methoddescribed herein.

The invention also comprises the use of a compound of the invention, ora pharmaceutically acceptable derivative thereof, in the manufacture ofa medicament for the treatment either acutely or chronically of cancer(including lymphoma and solid tumors, primary or metastatic, includingcancers such as noted elsewhere herein and including cancers which areresistant or refractory to one or more other therapies). Compounds ofthe invention can be useful in the manufacture of an anti-cancermedicaments. Compounds of the invention can also be useful in themanufacture of a medicament to attenuate or prevent disorders throughinhibition of one or more kinases such as ALK, jak2, b-raf, met, Tie-2,EGFR, FLT3, FAK, Pim-1, P13k, etc. . . . .

The invention further encompasses a composition comprising a compound ofthe invention, including a compound of any of the described classes orsubclasses, including those of any of the formulas noted above, amongothers, preferably in a therapeutically-effective amount, in associationwith a least one pharmaceutically acceptable carrier, adjuvant ordiluent.

Compounds of the invention can also be useful as standards and reagentsfor characterizing various kinases, especially but not limited to ALK,Met, Jak2, b-Raf, Tie-2, EGFR, FLT3 among others as well as for studyingthe role of such kinases in biological and pathological phenomena; forstudying intracellular signal transduction pathways mediated by suchkinases, for the comparative evaluation of new kinase inhibitors; andfor studying various cancers in cell lines and animal models.

3. Definitions

In reading this document, the following information and definitionsapply unless otherwise indicated.

The term “alkyl” is intended to include linear (i.e., unbranched oracyclic), branched, cyclic, or polycyclic non aromatic hydrocarbongroups, which are optionally substituted with one or more functionalgroups. Unless otherwise specified, “alkyl” groups contain one to eight,and preferably one to six carbon atoms. C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Lower alkyl refers toalkyl groups containing 1 to 6 carbon atoms. Examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyltert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may besubstituted or unsubstituted. Illustrative substituted alkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl,substituted phenethyl, etc.

The term “alkoxy” represents a subset of alkyl in which an alkyl groupas defined above with the indicated number of carbons attached throughan oxygen bridge. For example, “alkoxy” refers to groups —O-alkyl,wherein the alkyl group contains 1 to 8 carbons atoms of a linear,branched, cyclic configuration. Examples of “alkoxy” include, but arenot limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy,n-butoxy, s-pentoxy and the like.

“Haloalkyl” is intended to include both branched and linear chainsaturated hydrocarbon having one or more carbon substituted with aHalogen. Examples of haloalkyl, include, but are not limited to,trifluoromethyl, trichloromethyl, pentafluoroethyl and the like.

The term “alkenyl” is intended to include hydrocarbon chains of linear,branched, or cyclic configuration having one or more unsaturatedCarbon-carbon bonds that may occur in any stable point along the chainor cycle. Unless otherwise specified, “alkenyl” refers to groups usuallyhaving two to eight, often two to six carbon atoms. For example,“alkenyl” may refer to prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, andthe like. Furthermore, alkenyl groups may be substituted orunsubstituted.

The term “alkynyl” is intended to include hydrocarbon chains of eitherlinear or branched configuration, having one or more carbon-carbontriple bond that may occur in any stable point along the chain. Unlessotherwise specified, “alkynyl” groups refer refers to groups having twoto eight, preferably two to six carbons. Examples of “alkynyl” include,but are not limited to prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl,3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. Furthermore, alkynylgroups may be substituted or unsubstituted.

Cycloalkyl is a subset of alkyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 3 to 13 carbon atoms, any of whichis saturated. Examples of such cycloalkyl include, but are not limitedto cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane,and the like, which, as in the case of other alkyl moieties, mayoptionally be substituted. The term “cycloalkyl” may be usedinterchangeably with the term “carbocycle”.

Cycloalkenyl is a subset of alkenyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 3 to 13 carbon atoms, preferablyfrom 5 to 8 carbon atoms, which contains one or more unsaturatedcarbon-carbon double bonds that may occur in any point along the cycle.Examples of such cycloalkenyl include, but are not limited tocyclopentenyl, cyclohexenyl and the like.

Cycloalkynyl is a subset of alkynyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 5 to 13 carbon atoms, whichcontains one or more unsaturated carbon-carbon triple bonds that mayoccur in any point along the cycle. As in the case of other alkenyl andalkynyl moieties, cycloalkenyl and cycloalkynyl may optionally besubstituted.

The term “heteroalkyl” is meant a branched or unbranched alkyl, alkenyl,or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3or 4 heteroatoms independently selected from the group consisting of N,O, S, and P. Heteroalkyls include, without limitation, tertiary amines,secondary amines, ethers, thioethers, amides, thioamides, carbamates,thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates,sulfonamides, and disulfides. A heteroalkyl may optionally includemonocyclic, bicyclic, or tricyclic rings, in which each ring desirablyhas three to six members. The heteroalkyl group may be substituted orunsubstituted. Examples of heteroalkyls include, without limitation,polyethers, such as methoxymethyl and ethoxyethyl.

“Heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein refersto non-aromatic ring systems having five to fourteen ring atoms in whichone or more ring carbons, preferably one to four, are each replaced by aheteroatom such as N, O, or S. Heterocyclic groups may be substituted orunsubstituted and may include one, two, or three fused or unfused ringsystems. Non-limiting examples of heterocyclic rings include3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl,2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl,benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl,benzothiolanyl, and benzothianyl. A heterocylic group can include two ormore of the ring systems listed above. Also included within the scope ofthe term “heterocyclyl” or “heterocyclic”, as it is used herein, is agroup in which a non-aromatic heteroatom-containing ring is fused to oneor more aromatic or non-aromatic rings, such as in an indolinyl,chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radicalor point of attachment is on the non-aromatic heteroatom-containingring. The term “heterocycle”, “heterocyclyl”, or “heterocyclic” whethersaturated or partially unsaturated, also refers to rings that areoptionally substituted.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving six to fourteen ring atoms, such as phenyl, 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. An “aryl” ring may contain oneor more substituents. The term “aryl” may be used interchangeably withthe term “aryl ring”. “Aryl” also includes fused polycyclic aromaticring systems in which an aromatic ring is fused to one or more rings.Non-limiting examples of useful aryl ring groups include phenyl,hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl,trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl,phenanthro and the like, as well as 1-naphthyl, 2-naphthyl, 1-anthracyland 2-anthracyl. Also included within the scope of the term “aryl”, asit is used herein, is a group in which an aromatic ring is fused to oneor more non-aromatic rings, such as in a indanyl, phenanthridinyl, ortetrahydronaphthyl, where the radical or point of attachment is on thearomatic ring.

The term “heteroaryl” as used herein refers to stable heterocyclic, andpolyheterocyclic aromatic moieties having 5-14 ring atoms. Heteroarylgroups may be substituted or unsubstituted and may comprise one or morerings. Examples of typical heteroaryl rings include 5-memberedmonocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl,furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like;6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl and the like; and polycyclic heterocyclic ringgroups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, benzothiazole,benzimidazole, tetrahydroquinoline cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phenoxazinyl,and the like (see e.g. Katritzky, Handbook of Heterocyclic Chemistry).Further specific examples of heteroaryl rings include 2-furanyl,3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl,2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl,benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl,isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl.Heteroaryl groups further include a group in which a heteroaromatic ringis fused to one or more aromatic or nonaromatic rings where the radicalor point of attachment is on the heteroaromatic ring. Examples includetetrahydroquinoline, tetrahydroisoquinoline, andpyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidyl,imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyiridinyl,imidazo[1,2-c]pyrimidyl, pyrazolo[1,5-a][1,3,5]triazinyl,pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl,imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b][1,2,4]triazine, quinolyl,isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl,triazolopyrimidyl, pyridopyrazinyl. The term “heteroaryl” also refers torings that are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl group (including the aryl portion of an aralkyl, aralkoxy, oraryloxyalkyl moiety and the like) or heteroaryl group (including theheteroaryl portion of a heteroaralkyl or heteroarylalkoxy moiety and thelike) may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup include halogen (F, Cl, Br or I), alkyl, alkenyl, alkynyl,heteroalkyl, —CN, —OR², —S(O)_(r)R², (wherein r is an integer of 0, 1 or2), —SO₂ NR¹R², —NR¹R² , —O—NR¹R², —NR¹—NR¹R², —(CO)YR², —O—O(CO)YR²,—NR¹(CO)YR², —S(CO)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR², whereineach occurrence of Y is independently —O—, —S—, —NR¹—, or a chemicalbond; —(CO)YR² thus encompasses —C(═O)R², —C(═O)OR², and —C(═O)NR¹R².Additional substituents include —YC(═NR¹)YR², —YC(═N—OR¹)YR²,—YC(═N—NR¹R²)YR², —COCOR², —COMCOR² (where M is a 1-6 carbon alkylgroup), —YP(═O)(YR³)(YR³) (including among others —P(═O)(R³)₂),—Si(R^(3a))₃, —NO₂, —NR¹SO₂R² and —NR¹SO₂NR¹R². To illustrate further,substituents in which Y is NR¹ thus include among others, —NR¹C(═O)R²,—NR¹C(═O)NR¹R², —NR¹C(═O)OR², and —NR¹C(═NH)NR¹R². R³ substituent isselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heterocyclyl; R¹ and R² substituents ateach occurrence are independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heterocyclyl, and R¹, R² and R³ substituents may themselvesbe substituted or unsubstituted. Examples of substituents allowed on R¹,R² and R³ include, among others amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, aryl, heteroalkyl, heteroaryl,carbocycle, heterocycle, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy,alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, haloalkoxy groups.Additional illustrative examples include protected OH (such as acyloxy),phenyl, substituted phenyl, —O-phenyl, —O— (substituted) phenyl,-benzyl, substituted benzyl, —O-phenethyl (i.e., —OCH₂CH₂C₆H₅), —O—(substituted)phenethyl. Non-limiting illustrations of a substituted R¹,R² or R³ moiety include haloalkyl and trihaloalkyl, alkoxyalkyl,halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR², -M-SR² ,-M-NR¹R², -M-OC(O)NR¹R², -M-C(═NR²)NR¹R², -M-C(═NR¹)OR², -M-P(═O)(R³)₂,Si(R³a)₃, -M-NR¹C(O)R², -M-NR¹C(O)OR², -M-C(O)R², -M-C(═S)R²,-M-C(═S)NR¹R², -M-C(O)NR¹R², -M-C(O)NR²-M-NR¹R², -M-NR²C(NR¹)NR¹R²,-M-NR¹C(S)NR¹R², -M-S(O)₂R¹, -M-C(O)R¹, -M-OC(O)R¹, -MC(O)SR²,-M-S(O)₂NR¹R², —C(O)-M-C(O)R², -MCO₂R², -MC(═O)NR¹R², -M-C(═NH)NR¹R²,and -M-OC(═NH)NR¹R² (wherein M is a 1-6 carbon alkyl group).

Some more specific examples include but are not limited to chloromethyl,trichloromethyl, trifluoromethyl, methoxyethyl, alkoxyphenyl,halophenyl, —CH₂-aryl, —CH₂-heterocycle, —CH₂C(O)NH₂, —C(O)CH₂N(CH₃)₂,—CH₂CH₂OH, —CH₂OC(O)NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NEt₂, —CH₂OCH₃, —C(O)NH₂,—CH₂CH₂-heterocycle, —C(═S)CH₃, —C(═S)NH₂, —C(═NH)NH₂, —C(═NH)OEt,—C(O)NH-cyclopropyl, C(O)NHCH₂CH₂-heterocycle, —C(O)NHCH₂CH₂OCH₃,—C(O)CH₂CH₂NHCH₃, —CH₂CH₂F, —C(O)CH₂-heterocycle, —CH₂C(O)NHCH₃,—CH₂CH₂P(═O)(CH₃)₂, Si(CH₃)₃ and the like.

When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl)is substituted with a number of substituents varying within an expresslydefined range, it is understood that the total number of substituentsdoes not exceed the normal available valencies under the existingconditions. Thus, for example, a phenyl ring substituted with “n”substituents (where “n” ranges from 1 to 5) can have 1 to 5substituents, whereas it is understood that a pyridinyl ring substitutedwith “n” substituents has a number of substituents ranging from 1 to 4.The maximum number of substituents that a group in the compounds of theinvention may have can be easily determined.

An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, cycloalkyl,cycloalkenyl, cycloalkynyl or non-aromatic heterocyclic group may thusalso contain one or more substituents. Examples of suitable substituentson such groups include, but are not limited to those listed above forthe carbon atoms of an aryl or heteroaryl group and in addition includethe following substituents for a saturated carbon atom: ═O, ═S, ═NH,═NNR²R³, ═NNHC(O)R², ═NNHCO₂R², or ═NNHSO₂R², wherein R² and R³ at eachoccurrence are independently hydrogen, alkyl, alkenyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, aryl, heteroaryl,heterocyclyl.

Illustrative examples of substituents on an aliphatic, heteroaliphaticor heterocyclic group include amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, —CN,carboxy, alkoxycarbonyl, alkylcarbonyl, -OH, haloalkoxy, or haloalkylgroups.

Illustrative substituents on a nitrogen, e.g., in an heteroaryl ornon-aromatic heterocyclic ring include R¹, —NR¹R², —C(═O)R², —C(═O)OR²,—C(═O)SR², —C(═O)NR¹R², —C(═NR²)NR¹R², —C(═NR²)OR², —C(═NR¹)R³, —COCOR²,—COMCOR², —CN, —SO₂R², S(O)R², —P(═O)(YR³)(YR³), —NR¹SO₂R² and—NR¹SO₂NR¹R², wherein each occurrence of R³ is alkyl, alkenyl, alkynyl,cycloalkkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl andheterocyclyl; each occurrence of R¹ and R² is independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl and heterocyclyl.

When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl)is substituted with a number of substituents varying within an expresslydefined range, it is understood that the total number of substituentsdoes not exceed the normal available valencies under the existingconditions. Thus, for example, a phenyl ring substituted with “m”substituents (where “m” ranges from 0 to 5) can have 0 to 5substituents, whereas it is understood that a pyridinyl ring substitutedwith “m” substituents has a number of substituents ranging from 0 to 4.The maximum number of substituents that a group in the compounds of theinvention may have can be easily determined.

Certain compounds of the invention may exist in tautomeric forms, andthe invention includes all such tautomeric forms of those compoundsunless otherwise specified.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Thus, single stereochemicalisomers as well as enantiomeric and diastereomeric mixtures of thepresent compounds are within the scope of the invention. Thus, theinvention encompasses each diasteriomer or enantiomer substantially freeof other isomers (>90%, and preferably >95%, free from otherstereoisomers on a molar basis) as well as a mixture of such isomers.

Particular optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another method involves synthesisof covalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound.

Optically active compounds of the invention can be obtained by usingactive starting materials. These isomers may be in the form of a freeacid, a free base, an ester or a salt.

Compounds of the invention can exist in radiolabelled form, i.e., saidcompounds may contain one or more atoms containing an atomic mass ormass number different from the atomic mass or mass number: ordinarilyfound in nature. Radioisotopes of hydrogen, carbon, phosphorous,fluorine and chlorine include ³H, ¹⁴C, ³²P, ³⁵S, ¹⁸F and ³⁶Cl ,respectively. Compounds of the invention which contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of the invention. Tritiated, i.e., ³H, and carbon-14, i. e., ¹⁴C,radioisotopes are particularly preferred for their ease of preparationand detectability.

Radiolabelled compounds of the invention can generally be prepared bymethods well known to those skilled in the art. Conveniently, suchradiolabelled compounds can be prepared by carrying out the proceduresdisclosed herein except substituting a readily available radiolabelledreagent for a non-radiolabelled reagent.

4. Synthetic Overview

The practitioner has a well-established literature of heterocyclic andother relevant chemical transformations, recovery and purificationtechnologies to draw upon, in combination with the information containedin the examples which follow, for guidance on synthetic strategies,protecting groups, and other materials and methods useful for thesynthesis, recovery and characterization of compounds of the invention,including compounds containing the various choices for the R^(a), R^(b),R^(c), R^(d), R^(e), R^(b1), R^(c1), R^(d1), R^(e1), R^(f), R^(g), andRings A, B, C, D, E and F.

Various synthetic approaches may be used to produce the compoundsdescribed herein, including those approaches depicted schematicallybelow. The practitioner will appreciate that protecting groups may beused in these approaches. “Protecting groups”, are moieties that areused to temporarily block chemical reaction at a potentially reactivesite (e.g., an amine, hydroxy, thiol, aldehyde, etc.) so that a reactioncan be carried out selectively at another site in a multifunctionalcompound. In preferred embodiments, a protecting group reactsselectively in good yield to give a protected substrate that is suitablefor the planned reactions; the protecting group should be selectivelyremovable in good yield by readily available, preferably nontoxicreagents that do not unduly attack the other functional groups present;the protecting group preferably forms an readily separable derivative(more preferably without the generation of new stereogenic centers); andthe protecting group preferably has a minimum of additionalfunctionality to avoid the complication of further sites of reaction. Awide variety of protecting groups and strategies, reagents andconditions for deploying and removing them are known in the art. See,e.g., “Protective Groups in Organic Synthesis” Third Ed. Greene, T.W.and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999. For additionalbackground information on protecting group methodologies (materials,methods and strategies for protection and deprotection) and othersynthetic chemistry transformations useful in producing the compoundsdescribed herein, see in R. Larock, Comprehensive organicTransformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995). The entire contents of these references are hereby incorporatedby reference.

Also, one may chose reagents enriched for a desired isotope, e.g.deuterium in place of hydrogen, to create compounds of the inventioncontaining such isotope(s). Compounds containing deuterium in place ofhydrogen in one or more locations, or containing various isotopes of C,N, P and O, are encompassed by the invention and may be used, forinstance, for studying metabolism and/or tissue distribution of thecompounds or to alter the rate or path of metabolism or other aspects ofbiological functioning.

Compounds of the invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or by a variation thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto those described below. The reactions are preformed in a solventappropriate to the reagents and materials employed and suitable for thetransformation being effected. It will be understood by those skilled inthe art of organic synthesis that the functionality present on themolecule should be consistent the transformations proposed. This willsometimes required some judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention.

A compound of the invention could be prepared as outlined from Scheme 1to Scheme 57a and via standard methods known to those skilled in theart. For certain compounds of the invention, microwave-assistedsynthesis may be carried out using conventional procedures and theconditions noted in the examples which follow. Reactions may be carriedout using commercially available microwave reactors such as the BiotageInitiator 2.0™ (Biotage AB, Kungsgatan 76, SE-753 18 Uppsala, Sweden or1725 Discovery Drive Charlottesville, Va. 22911) or the CEM Discover™System (CEM Corporation, Matthews, N.C.) which were used in the examplesbelow.

A compound of Formula Ia or VIA in which n is 0 and X is N can beprepared in a 2 steps synthesis as shown in Scheme 1. A [Ring A] moietycan first be incorporated to the central pyrimidine moiety by reacting[Ring A]-NH₂ with 2,4-dichloro-5-(trifluoromethyl)pyrimidine in thepresence of a base such as di-isopropylethyl amine at high temperaturegenerating intermediate 1. The [Ring E]-L- moiety can then beincorporated onto intermediate 1 using various conditions depending onthe nature of the L linker. The variables in the intermediate [RingE]-[L]- and [Ring A] are as defined previously, Rings A and E beingsubstituted with permitted R^(a) and R^(g) groups respectively.

An approach to the preparation of an intermediate 1 is illustrated belowin Scheme IA in which Ring A is a phenyl:

A compound of Formula VIA in which L is O can be prepared usingmicrowave chemistry, by reacting an intermediate 1 with [Ring E]-OH in asolvent such as dimethylformamide and high temperatures as shown inScheme 2.

An approach to the preparation of a compound of Formula VIA in which Lis O, is illustrated below in Scheme 2A in which Ring A and Ring E arephenyls:

A compound of Formula VIA in which L is NH can be prepared usingmicrowave chemistry, by reaction an intermediate 1 with [Ring E]-NH₂, ina polar solvent such as Ethanol, and using high temperatures, as shownin Scheme 3. A base (i.e. di-isopropylethyl amine, triethylamine or thelike) or an acid may be added to facilitate the displacement reaction.

An approach to the preparation of a few compounds of Formula VIA inwhich L is NH, is illustrated below in Scheme 3A and 3B in which E is aphenyl or adamantanamine:

A compound of Formula VIA in which L is NH(CH₂)₁₋₄ can be prepared usingmicrowave chemistry, by reaction an intermediate 1 with [RingE]-(CH₂)₁₋₄NH₂, in the presence of a base such as triethylamine, in apolar solvent such as Ethanol, and using high temperatures, as shown inScheme 4:

An approach to the preparation of a few compounds of Formula VIA inwhich L is NH(CH₂)₁₋₄, is illustrated below in Schemes 4A and 4B. Scheme4A illustrates the synethesis of a compound of Formula VIa in which E isa phenyl and L is NHCH₂ and Scheme 4B illustrates the synthesis of acompound of Formula VIA in which E is 3-1H-indole and L is NH(CH₂)₂:

A compound of Formula VIA in which L is SH(CH₂)y can be prepared usingmicrowave chemistry, by reaction an intermediate 1 with [RingE]-(CH₂)_(y)SH, in the presence of a base such as Cesium carbonate, andin a solvent such as dimethylformamide at high temperatures, as shown inScheme 5. The variable y is defined above.

An approach to the preparation of a compound of Formula VIa in which Lis S(CH₂)_(y), is illustrated below in Scheme 5A:

A compound of Formula VIA in which L is bond and [Ring E] is an aryl orheteroaryl, can be prepared using Suzuki coupling conditions. Scheme 6illustrates the Suzuki coupling reaction.

In a non limiting example, Scheme 6A illustrates the preparation of acompound of Formula VIA in which L is a bond and [Ring E] is a phenyl.

A compound of Formula VIA in which L is bond and [Ring E] is a N-linkedheterocyclyl, can be prepared using microwave chemistry, by reaction anintermediate 1 with the heterocyclyl, in the presence of a base such astriethylamine, in a polar solvent such as Ethanol, and using hightemperatures, as shown in Scheme 7:

In a non limiting example, Scheme 7A illustrates the preparation of acompound of Formula VIA in which L is a bond and [Ring E] isN-phenyl-piperazine.

An alternative reaction sequence can be used for the preparation ofcompounds of Formula VIa in which L is NH. [Ring E]-NH moiety can befirst incorporated to the central pyrimidine moiety prior to theincorporation of [Ring A]-NH moiety. Scheme 8 illustrates the reactionof 2,4,5-trichloropyrimidine with a [Ring-E]-NH₂ moiety in the presenceof a base (i.e. potassium carbonate or sodium hydride or the like) in asolvent such as dimethyformamide or Ethanol in order to generateintermediate 2. The reaction can be perform at room temperature or mayrequire higher temperature.

Another example of this reaction is shown below in Scheme 9 in whichintermediate 3 is prepared by reacting2,4-dichloro-5-(trifluoromethyl)pyrimidine with a [Ring E]-NH₂ moiety inthe presence of sodium hydride in dimethylformamide at lowertemperatures.

Intermediate 2 or 3 can then be reacted with a [Ring-A]—(CH₂)_(n)NH₂moiety using regular displacement conditions as shown below in Scheme10.

In a non limiting example, Schemes 10A and 10B illustrate thepreparation of compounds of Formula VIA in which L is NH and Ring A andRing E are substituted phenyl:

The synthetic guidance provided in Schemes 1 through 10 is applicable toa variety of Ring A and Ring E of the invention and allows thepreparation of all compounds of the invention.

Scheme 11 illustrates the preparation of a compound of Formula IA andVIA in which n is 0, L is NH and X¹ is CH.

In Scheme 11, [Ring E]-NH moiety is incorporated onto the pyridinecentral scaffold by reacting 2-chloro-4-iodo-5-(trifluoromethyl)pyridinewith [Ring E]-NH₂ using Palladium coupling reaction conditions. [RingA]-NH moiety is then incorporated by displacement chemistry aspreviously described in the above Schemes. Microwaves and heat can alsobe used to accelerate or drive the displacement reaction to completion.

In a non limiting example, Scheme 11A illustrates the preparation ofcompounds of Formula VIA in which L is NH, X¹ is CH, and Ring A and RingE are substituted phenyl.

Scheme 12 illustrates the synthesis of a compound of Formula IVA inwhich X¹ is CH and R^(d) and R^(e) form a phenyl ring.

In a non limiting example, Scheme 12A illustrates the preparation ofcompounds of Formula IVA in which X¹ is CH and R^(d) and R^(e) form aphenyl ring, Ring A and Ring E are substituted phenyl.

Scheme 13 illustrates the synthesis of a compound of Formula IIIA inwhich X¹ is CH and R^(b) and R^(c) form a phenyl ring which is furthersubstituted with a phenyl ring.

In a non limiting example, Scheme 13A illustrates the preparation ofcompounds of Formula VA in which X¹ is CH and R^(b) and R^(c) form aphenyl ring, Ring A is substituted phenyl and R^(f) is a substitutedphenyl.

Scheme 14 illustrates the synthesis of a compound of Formula IIIA inwhich X¹ is N and R^(c) and R^(d) form a pyrrole.

in which Ring A and R^(a) are as defined in part 1 and in R—X, R isalkyl, heteroaryl, aryl, aryl alkyl, heteroaryl alkyl, heterocyclyl andother groups selected from the R^(f) list of substituents; and X is ahalide or other leaving groups.

Another example of preparation of a compound of Formula IIIA isillustrated below in Scheme 15 in which substituent R depicted in scheme14 is a phenyl.

in which R¹ is a substituent selected from R^(f) list and Ring A andR^(a) are defined in part 1.

In a non limiting example, Scheme 15A illustrates the preparation ofcompounds of Formula IIIA in which X¹ is N, R^(c) and R^(d) form apyrrole, Ring A is a substituted phenyl and R^(f) is a substitutedphenyl:

In a non limiting example, Scheme 16 illustrates the preparation ofcompounds of Formula IIIA in which X¹ is N and R^(c) and R^(d) form animidazole ring which is substituted with a phenyl.

in which R¹ is a substituent selected from R^(f) list and Ring A andR^(a) are defined in part 1.

For the compounds of the invention, one of R^(a), R^(b), R^(b1), R^(e),R^(c1), R^(d), R^(d1), R^(e), R^(e1), R^(f) or R^(g) when present, is orcontains —P(═O)(R³)₂.

Schemes 17 to 24 illustrate the preparation of phosphorous containingsubstituents and phosphorous containing moieties of current interest.

Scheme 17 illustrates the preparation of a [Ring A]-NH₂ moiety in whichRing A is a pyridine substituted with —P(═O)(R³)₂.

in which R³ is defined in part 1. A similar synthetic route could beused to introduce a —P(═O)(R³)₂ substituent onto a phenyl or heteroarylring whether the ring is Ring A or Ring E. This synthetic scheme alsoillustrates the preparation of a [Ring E]-L moiety in which L is NH andRing E is aryl or heteroaryl. This scheme can be used for the synthesisof compounds of the invention of Formulae I to VI.

Of other interest are compounds in which R^(a) substituent isphosphorous containing substituent. Scheme 18 illustrates the synthesisof an intermediate [Ring A]-NH₂ in which Ring A is a phenyl substitutedwith —P(═O)(CH₃)₂.

Scheme 19 illustrates the preparation of a [Ring A]-NH₂ intermediate inwhich Ring A is a phenyl substituted with (CH₂)_(m)—P(═O)(R³)₂ and mis 1. This scheme is useful for the synthesis of compounds of FormulaeII and IIA.

Scheme 20 illustrates the preparation of a [Ring A]-NH₂ moiety in whichRing A is a bicyclic structure such as naphthalene substituted withR^(f) being —P(═O)(R³)₂.

This scheme could also be used to prepare a [Ring E]-L moiety in whichRing E is naphthalene, L is NH and R^(g) is —P(═O)(R³)₂ This scheme canalso be used for the synthesis of compounds of the invention of FormulaeVIIA.

Scheme 21 illustrates the synthesis of [Ring A]-(CH₂)_(n)—NH₂intermediate in which Ring A is phenyl substituted with —P(═O)(R³)₂ andn is 1.

Scheme 21 can also be used for the synthesis of a [Ring E]-L moiety inwhich L is CH₂NH and Ring E is a phenyl substituted with —P(═O)(R³)₂

In some embodiment, a R^(a) , R^(f) or R^(g) containing —P(═O)(R³)₂substituent can be of cyclic structure.

Schemes 22 to 23 illustrate the synthesis of cyclic structures ofinterest containing —P(═O)(R³)₂.

Scheme 22 illustrates the preparation of cyclic substituent R^(a) (orR^(f) or R^(g)) containing —P(═O)(R³)₂.

Schemes 22A and 22B illustrate the incorporation of this cyclicsubstituent onto a Ring A or Ring E.

Scheme 22A illustrates the synthesis of a [Ring A]-NH₂ moiety in whichRing A is a phenyl substituted with a methoxy group and with a—P(═O)(R³)₂ containing cyclic substituent. This scheme could also beused for the synthesis of a [Ring E]-L moiety in which L is NH and RingE is a phenyl substituted with a methoxy group and with a —P(═O)(R³)₂containing cyclic substituent.

Scheme 23 illustrates the synthesis of a [Ring A]-NH₂ intermediate inwhich Ring A is phenyl substituted by methoxy and a —P(═O)(R₃)₂ group inwhich the two R³ groups form with the phosphorous atom to which they areattached 6-membered saturated ring.

Scheme 24 illustrates the synthesis of a piperazine substituent which isfurther substituted with —CH₂P(═O)(CH₃)₂. This scheme can be used forthe synthesis of [Ring A]-NH₂ intermediate in which Ring A is a phenylsubstituted with a phosphorous containing piperazine group. It couldalso be used for the synthesis of a compound of any of the Formulae ofthe invention in which one of the substituents (R^(a), R^(b), R^(e),R^(d), R^(e), R^(f) or R^(g)) is NR¹R² and NR¹R² form a piperazine ringsubstituted with —CH₂P(═O)(CH₃)₂.

A compound of Formula IB or VI can be prepared in a 2 steps synthesis asshown in Scheme 1. A [Ring A] moiety can first be incorporated to thecentral pyrimidine moiety by reacting [Ring A]-NH₂ with a substituted orunsubstituted 4,6-dichloropyrimidine in the presence of a base such asdi-isopropylethyl amine at high temperature generating intermediate 1a.The [Ring E]-L- moiety can then be incorporated onto intermediate lausing various conditions depending on the nature of the L linker. Thevariables in the intermediate [Ring E]-[L]- and [Ring A] are as definedpreviously, Rings A and E being substituted with permitted R^(a) andR^(g) groups respectively.

An approach to the preparation of an intermediate 1a is illustratedbelow in Scheme 1A in which Ring A is a phenyl:

A compound of Formula IB or VII in which L is NH can be prepared usingmicrowave chemistry, by reacting an intermediate la with [Ring E]-NH₂ ina solvent such as n-Butanol under acidic conditions as shown in Scheme26.

An approach to the preparation of a compound of Formula VI in which L isNH, is illustrated below in Scheme 26A in which Ring A and Ring E arephenyls:

A compound of Formula TB or VII in which L is bond and [Ring E] is aN-linked heterocyclyl, can be prepared by reacting an intermediate 1awith the heterocyclyl, in the presence of a base such asdi-isopropyldiethylamine, in a polar solvent such as iso-propanol, andusing high temperatures, as shown in Scheme 27:

In a non limiting example, Scheme 27A illustrates the preparation of acompound of Formula VII or IB in which R^(c) is [L]-[Ring E] in which Lis a bond and [Ring E] is N-phenyl-piperazine.

A compound of Formula IB or VII in which R^(c) is [L]-[Ring E] with Lbeing O can be prepared by reacting 4,6-dichloropyrimidine with anoptionally substituted phenol; in the presence of sodium hydride in asolvent such as dimethylformamide as shown in Scheme 28. A [Ring A]moiety can then be incorporated to the central pyrimidine moiety byreacting [Ring A]—(CH₂)—NH₂ in the presence of a base (i.e.di-isopropylethyl amine, triethylamine or the like) or an acid in orderto facilitate the displacement reaction.

An approach to the preparation of a few compounds of Formula IB or VIIin which L is NH, is illustrated below in Scheme 28A in which Ring A andRing E are phenyls:

A compound of Formula IB or VII in which L is NH(CH₂)₁₋₄ can be preparedusing microwave chemistry, by reaction an intermediate 1a with [RingE]—(CH₂)₁₋₄NH₂, in the presence of a base such as triethylamine, in apolar solvent such as Ethanol, and using high temperatures, as shown inScheme 29:

An approach to the preparation of a few compounds of Formula VII inwhich L is NH(CH₂)₁₋₄, is illustrated below in Schemes 29A and 29B.Scheme 29A illustrates the synethesis of a compound of Formula VII inwhich Ring E is a phenyl and L is NHCH₂ and Scheme 29B illustrates thesynthesis of a compound of Formula VII in which Ring E is 3-1H-indoleand L is NH(CH₂)₂:

A compound of Formula IB and VII in which L is SH(CH₂)y can be preparedusing microwave chemistry, by reaction an intermediate la with [RingE]—(CH₂)_(y)SH, in the presence of a base such as Cesium carbonate, andin a solvent such as dimethylformamide at high temperatures, as shown inScheme 30. The variable y is defined above.

An approach to the preparation of a compound of Formula VII in which X³is CH, X² is N, L is S(CH₂)_(y) and Rings A and E are substitutedphenyls, is illustrated below in Scheme 30A:

A compound of Formula IB or VII in which L is bond and [Ring E] is anaryl or heteroaryl, can be prepared using Suzuki coupling conditions.Scheme 31 illustrates the Suzuki coupling reaction.

In a non limiting example, Scheme 31A illustrates the preparation of acompound of Formula VII in which X³ is CH, X² is N, L is a bond and[Ring E] and [Ring A] are phenyl.

A compound of Formula IC or VI in which R^(c) is [L]-[Ring E] with Lbeing O, can be prepared in a 2 steps synthesis as shown in Scheme 32. A[Ring E]-L- moiety can first be incorporated to the central pyridazinemoiety by reacting [Ring E]-OH with a substituted or unsubstituted3,5-dichloropyridazine in the presence of a base such as sodium hydridegenerating intermediate 2a. The [Ring A]-(CH₂)—NH₂ moiety can then bereacted with intermediate 2a in the presence of a base (i.e.di-isopropylethyl amine, triethylamine or the like) or an acid in orderto facilitate the displacement reaction.

In a non limiting example, Scheme 32A illustrates the preparation of acompound of Formula VII in which L is O, X³ is N, X² is CH and [Ring E]and [Ring A] are substituted phenyl.

A compound of Formula IC in which R^(c) is [L]-[Ring E] with L beingNH(CH₂)_(y), can be prepared in 4 steps as shown in Scheme 33. A [RingE]-(CH₂)_(y)—NH₂ moiety can first be incorporated to the centralpyridazine moiety by reacting [Ring E]-(CH₂)_(y)—NH₂ with4,5-dichloropyridazin-3(2H)-one in the presence of triethylamine in asolvent such as Ethanol generating intermediate 3a. Intermediate 3a isthen hydrogenated and reduced with phosphoric trichloride generatingintermediate 4a. The [Ring A]-(CH₂)—NH₂ moiety can then be reacted withintermediate 4a in the presence of a base (i.e. di-isopropylethyl amine,triethylamine or the like) or an acid in order to facilitate thedisplacement reaction.

In a non limiting example, Scheme 33A illustrates the preparation of acompound of Formula VII in which L is NH, X³ is N, X² is CH and [Ring E]and [Ring A] are substituted phenyl.

In a similar way, a compound of Formula IC or VI in which R^(c) is[L]-[Ring E] with L being O, can be prepared by reacting [Ring E]-OHwith 4,5-dichloropyridazin-3(2H)-one in the presence of potassiumcarbonate; followed by the same sequence of steps as described in Scheme33. This alternative synthesis is illustrated in Scheme 34:

In a similar way, a compound of Formula IC in which R^(c) is a N-linkedheterocyclyl can be prepared by reacting a heterocyclyl such as asubstituted piperidine with 4,5-dichloropyridazin-3(2H)-one followed bythe same sequence of steps as described in Scheme 9. This synthesis isillustrated in Scheme 35:

Scheme 36 illustrates the synthesis of a compound of Formula IIIA inwhich R^(e) and R^(b) are H and R^(c) and R^(d) form an imidazolesubstituted with a phenyl group.

in which R is a substituent selected from R^(f) and Ring A, Ra and n aredefined above.

In a non limiting example, Scheme 36A illustrates the preparation ofcompounds of Formula IIIA in which R^(c) and R^(d) form an imidazole,Ring A is a substituted phenyl and R^(f) is a substituted phenyl:

A compound of Formula I, IB, IIB or VIA in which n is 0 can be preparedin a 2 steps synthesis as shown in Scheme 37. A [Ring A] moiety canfirst be incorporated to the central triazine moiety by reacting [RingA]-Br with 5-chloro-6-substituted-1,2,4-triazin-3-amine under BuchwaldHartwig cross coupling conditions to generate intermediate 1 (I-1). The[Ring E]-L- moiety can then be incorporated onto I-1 using variousconditions depending on the nature of the L linker. The variables in theintermediate [Ring E]-[L]- and [Ring A] are as defined previously, RingsA and E being substituted with permitted R^(a) and R^(g) groupsrespectively.

An approach to the preparation of an intermediate 1c is illustratedbelow in Scheme 37A in which Ring A is a phenyl:

Intermediate I-la is then reacted with a substituted aniline, asillustrated in Scheme 37B, to generate compound of Formula VIA in whichL is NH, Ring A and Ring E are phenyl, n is 0, and R^(d) is methyl.

Intermediate I-1a can also be reacted with a substituted phenol orthiophenol, as illustrated in Scheme 37C, to generate compound ofFormula VIA in which L is O or S, Ring A and Ring E are phenyl, n is 0,and R^(d) is methyl.

An alternative synthesis to compounds of Formula I, IB, IIB or VIA isillustrated in Scheme 38. [Ring E]-LH moiety, in which L is O, S or NH,can be first incorporated to the central triazine moiety prior to theincorporation of [Ring A]-NH moiety. Schemes 38 and 39 illustrates thereaction of 3,5-dichloro-6-substituted-1,2,4-triazine with a [Ring-E]-LHmoiety in the presence of a base (for example triethyamine, potassiumcarbonate, sodium carbonate or sodium hydride or the like) in a suitablesolvent such as for example dimethylformamide, methylene chloride ortetrahydrofuran in order to generate intermediate I-2 and I-3. Thereaction can be performed at room temperature or may require highertemperature. Intermediates I-2 and I-3 are then reacted with a [RingA]-NH₂ moiety under acidic conditions (i.e Camphor sulfonic acid) in thepresence of a suitable solvent such as for example tetrahydrofuran athigh temperature. This sequence of reactions is described in PCTapplication WO 2006/015985.

When R^(d) is chloro, 3,5,6-trichloro-1,2,4-triazine, can be preparedaccording to methods described in PCT patent application WO 2004/074266,by reacting 1,2,4-triazine-3,5(2H,4H)dione with bromine in a presence ofa suitable solvent, such as for example water, to generate anintermediate of Formula I-4a. Synthesis of3,5,6-trichloro-1,2,4-triazine is illustrated in Scheme 40. IntermediateI-4a is then reacted with POCl₃ and PCl₅ in the presence of a base suchas for example N,N-diethylaniline.

When R^(d) is Methyl, 3,5-dichloro-6-methyl-1,2,4-triazine can beprepared according to methods described in PCT patent application WO2005/054199.

When R^(d) is H; 3,5-dichloro-1,2,4-triazine can be prepared accordingto methods described in Journal of Organic Chemistry, 23, 1522-4; 1958in which 1,2,4-triazine-3,5(2H,4H)dione is reacted with POCl₃. Thesynthesis of 3,5-dichloro-1,2,4-triazine is illustrated in Scheme 41.

A compound of Formula I, IA, IC, TIC or VIB can be prepared in a 2 stepssynthesis as shown in Scheme 42. A [Ring A]-(CH₂)_(n) NH— moiety canfirst be incorporated to the central triazine moiety by reacting [RingA]-(CH₂)_(n)NH₂ with 2,4-dichloro-6-substituted-1,3,5-triazine in thepresence of a base as for example di-isopropylethylamine in a suitablesolvent. The [Ring E]-L- moiety can then be incorporated onto 1-6 usingvarious conditions depending on the nature of the L linker. Thevariables in the intermediate [Ring E]-[L]- and [Ring A] are as definedpreviously, Rings A and E being substituted with permitted R^(a) andR^(g) groups respectively.

When R^(e) is methyl, 2,4-dichloro-6-methyl-1,3,5-triazine can beprepared according to methods described in Bioorganic MedicinalChemistry letters 16(21), 5664-5667, 2006.2,4,6-trichloro-1,3,5-triazine is reacted with methyl magnesium bromideto generate 2,4-dichloro-6-methyl-1,3,5-triazine as illustrated inScheme 42A.

In a non limiting example, an intermediate of formula 1-6 in which R^(e)is H, n is 0 and Ring A is phenyl is illustrated in Scheme 42B:

A compound of Formula VIB in which L is O can be prepared usingmicrowave chemistry, by reacting an intermediate I-6 with [Ring E]-OH ina solvent such as dimethylformamide and high temperatures as shown inScheme 43.

An approach to the preparation of a compound of Formula VIB in which Lis 0, is illustrated below in Scheme 43A in which Ring A and Ring E arephenyls:

A compound of Formula VIB in which L is NH can be prepared usingmicrowave chemistry, by reaction an intermediate I-6 with [Ring E]-NH₂,in a polar solvent such as Ethanol, and using high temperatures, asshown in Scheme 44. A base (i.e. di-isopropylethyl amine, triethylamine,or the like) or an acid may be added to facilitate the displacementreaction. A similar displacement reaction is described in PCT patentapplication WO 2005/047279.

An approach to the preparation of a few compounds of Formula VIB inwhich L is NH, is illustrated below in Scheme 44A and 44B in which RingE is a phenyl or adamantane respectively:

A compound of Formula VIB in which L is NH(CH₂)₁₋₄ can be prepared usingmicrowave chemistry, by reaction an intermediate I-6 with [RingE]-(CH₂)₁₋₄NH₂, in the presence of a base such as triethylamine, in apolar solvent such as Ethanol, and using high temperatures, as shown inScheme 45:

An approach to the preparation of a few compounds of Formula VIB inwhich L is NH(CH₂)₁₋₄, is illustrated below in Schemes 45A and 45B.Scheme 45A illustrates the synthesis of a compound of Formula VIB inwhich R^(e) is Cl, Ring E is a phenyl and L is NHCH₂ and Scheme 45Billustrates the synthesis of a compound of Formula VIB in which R^(e) isCl, Ring E is 3-1H-indole and L is NH(CH₂)₂:

A compound of Formula VIB in which L is SH(CH₂)_(y) can be preparedusing microwave chemistry, by reaction an intermediate I-6 with [RingE]—(CH₂)_(y)SH, in the presence of a base such as Cesium carbonate, andin a solvent such as dimethylformamide at high temperatures, as shown inScheme 46. The variable y is defined above.

An approach to the preparation of a compound of Formula VIB in which Lis S(CH₂)_(y), is illustrated below in Scheme 46A:

A compound of Formula VIB in which L is bond and [Ring E] is an aryl orheteroaryl, can be prepared using Suzuki coupling conditions. Scheme 11illustrates the Suzuki coupling reaction. The displacement of one of thechlorine by and aryl Grignard or and aryl boronic acid is described inPCT patent application WO 01/25220 and Helv. Chim. Acta, 33, 1365(1950). The displacement of one of the chlorines by a heteroaryl ring isdescribed in WO 01/25220, J. Het. Chem., 11, 417 (1974); and Tetrahedron31, 1879 (1975). These reactions can be facilitated by using Microwavechemistry. Microwave assisted Suzuki coupling reaction is also describedin Journal of Medicinal Chemistry, 2007, 50(17), 3497.

When R^(e) is chloro, the Suzuki reaction is also described in PCTpatent application WO 2002/22605.

In a non limiting example, Scheme 47A illustrates the preparation of acompound of Formula VIB in which L is a bond and [Ring E] is asubstituted phenyl.

A compound of Formula I, IB or VIA in which L is a bond and Ring E is anaryl or heteroaryl ring, can also be prepared in a similar way usingSuzuki coupling conditions. A similar sequence of reaction is describedin PCT patent application WO 2005/054199 and is illustrated below inScheme 48:

A compound of Formula VIA in which L is bond and [Ring E] is a N-linkedheterocyclyl, can be prepared using microwave chemistry, by reaction anintermediate I-6 with the heterocyclyl, in the presence of a base suchas triethylamine, in a polar solvent such as Ethanol, and using hightemperatures, as shown in Scheme 49. A similar displacement is describedin PCT patent application WO 2005/059668.

In a non limiting example, Scheme 49A illustrates the preparation of acompound of Formula VIA in which L is a bond, R^(e) is Cl and [Ring E]is N-phenyl-piperazine.

Scheme 50 illustrates the preparation of a compound of Formula IVA inwhich R^(e) is L-[Ring E]; L is NH, X³ is N, X⁴ is C and Ring C is atriazole. A similar sequence of reaction is described in Bioorganic &Medicinal Chemistry Letters, 16(5), 1353-1357; 2006. Microwave chemistrycan also be used to accelerate the displacement reaction.

In a non limiting example, Scheme 50A illustrates the preparation ofcompounds of Formula IVA in which L is NH, X³ is N, X⁴ is C, Ring C is atriazole, and Ring A and Ring E are substituted phenyl.

An alternative route to compounds of Formula IVA in which Ring C is atriazole is illustrated in Scheme 51. A compound of Formula I-15 can bereacted with an aryl halide (such as aryl bromide) or heteroaryl halidein the presence of a base, such as for example Cesium carbonate, and inthe presence of a palladium acetate and a phosphorous ligand (i.e.xanphos); which generates intermediate I-15a. Intermediate I-15a is thensubjected to m-CPBA and the oxidized sulfur is displaced with a RingA-NH₂ moiety. The synthesis of intermediate I-15 is described in Journalof heterocyclic chemistry, 37(6), 1587-1590, 2000.

In a non limiting example, Scheme 51A illustrates the preparation ofcompounds of Formula IVA in which R^(c) is L-[Ring E], and L is NH, X³is N, X⁴ is C, Ring C is a triazole, R^(f) is Me and Ring A and Ring Eare substituted phenyl.

Scheme 52 illustrates the synthesis of a compound of Formula IVA inwhich X³ is N, X⁴ is C and Ring C is a pyrazole. Thepyrazolo[1,5-a][1,3,5]triazine ring system can be prepared from thestarting amino pyrazole as shown in Scheme 52. Synthesis of variousamino pyrazoles and cyclization conditions are described in US patentapplication US 2008/187219 and Biorganic & Medicinal Chemistry letters,17(15), 4191-4195, 2007.

In a non limiting example, Scheme 52A illustrates the preparation ofcompounds of Formula IVA in which X³ is N, X⁴ is C, Ring C is apyrazole, Ring A and Ring E are substituted phenyl.

Scheme 53 illustrates the synthesis of a compound of Formula IVA inwhich X⁴ is N and X³ is C, R^(c) is L-[Ring E], L is NH and [Ring C] isa pyrrole. This synthesis is described in PCT application WO2008/057994.

In a non limiting example, Scheme 53A illustrates the preparation ofcompounds of Formula IVA in which X⁴ is N and X³ is C, R^(e) is L-[RingE], L is NH and [Ring C] is a pyrrole; and Ring A and Ring E aresubstituted phenyl.

Scheme 54 illustrates the synthesis of a compound of Formula IIIA inwhich Ring B is a pyrrole.3,6-Dichloro-N-substituted-1,2-4-triazin-5-amine is reacted with asubstituted alkyne under Sonogashira conditions to generate3-chloro-5-substituted-pyrrolo[2,3-e][1,2,4]triazine. A similarsynthetic route using Sonogashira reaction is described in TetrahedronLetters, 48(29), 5069-5072; 2007.

in which Ring A and R^(a), n and s are as defined in part 1 and R and R′are alkyl, heteroaryl, aryl, aryl alkyl, heteroaryl alkyl, heterocyclyland other groups selected from the R^(f) list of substituents. Examplesof R′ are methyl, ethyl, methyl dialkylamino, phenyl and the like.Examples of R are substituted phenyl, substituted benzyl, substitutedpyridine and the like.

In a non limiting example, Scheme 54A illustrates the preparation ofcompounds of Formula IIIA in which Ring B is a pyrrole; R′ is a methylgroup, R is a substituted phenyl and Ring A is a substituted phenyl.

Another example of preparation of a compound of Formula IIIA isillustrated below in Scheme 55 in which Ring B is an imidazole. Anintermediate I-19 can be reacted with an amine to generate intermediateI-19a and the cyclization occurs in the presence of SOCl₂ andtrimethoxymethane and generates intermediate I-19b. The cyclization stepis described in Liebigs Annalen der Chemie, 7, 631-40, 1990. The methylthioether in intermediate I-19b can then be oxidized with m-CPBA anddisplaced with a [Ring A]-(CH₂)_(n)NH₂ moiety as previously described inScheme 52.

in which R is alkyl, heteroaryl, aryl, aryl alkyl, heteroaryl alkyl,heterocyclyl and other groups selected from the R^(f) list ofsubstituents. Examples of R are methyl, ethyl, methyl dialkylamino,phenyl and the like. Examples of R are substituted phenyl, substitutedbenzyl, substituted pyridine and the like. Ring A and R^(a) are definedin part 1.

In a non limiting example, Scheme 55A illustrates the preparation ofcompounds of Formula IIIA in which Ring B is an imidazole, Ring A is asubstituted phenyl and R is a substituted phenyl:

Another example of preparation of a compound of Formula IIIA isillustrated below in Scheme 56 in which Ring B is a pyrazole. Anintermediate I-20 can be reacted with hydrazinecarbothioamide and thecyclization occurs in the presence of potassium carbonate whichgenerates intermediate I-20a. The cyclization step is described inJournal of Heterocyclic Chemistry, 21(3), 923-6, 1984. IntermediateI-20a is then reacted with a [Ring]A-(CH₂)_(n)NH₂ moiety. A similardisplacement is described in Journal fuer Praktische Chemie (Leipzig),326(6), 994-8, 1984.

in which R″ is a substituent selected from R^(f) list and Ring A andR^(a) are defined in part 1.

In a non limiting example, Scheme 56A illustrates the preparation ofcompounds of Formula IIIA in which Ring B is a pyrazole, Ring A is asubstituted phenyl and R″ is a methoxy group.

Another example of preparation of a compound of Formula IIIA isillustrated below in Scheme 57 in which Ring B is a phenyl. Asubstituted 2-nitroaniline can undergo cyclization in the presence ofRaney Nickel as described in Bioorganic & Medicinal Chemistry Letters,17(21), 5818, 2007. When 2-nitroaniline is substituted with a bromide orhalide, a Suzuki coupling reaction can be used to introduce an aryl orheteroaryl onto the fused phenyl ring B. The Ring A-NH₂ moiety can beintroduced using Buchwald-Hartwig cross-coupling reaction.

In a non limiting example, Scheme 57A illustrates the preparation ofcompounds of Formula IIIA in which Ring B and Ring A are substitutedphenyl:

With synthetic approaches such as the foregoing, combined with theexamples which follow, additional information provided herein andconventional methods and materials, the practitioner should be able toprepare the full range of compounds disclosed herein.

5. Uses, Formulations, Administration Pharmaceutical Uses; Indications

The invention features compounds having biological properties which makethem of interest for treating or modulating disease in which kinases maybe involved, symptoms of such disease, or the effect of otherphysiological events mediated by kinases. For instance, a number ofcompounds of the invention have been shown to inhibit tyrosine kinaseactivity of ALK, fak and c-met, among other tyrosine kinases which arebelieved to mediate the growth, development and/or metastasis of cancer.A number of compounds of the invention have also been found to possesspotent in vitro activity against cancer cell lines, including amongothers karpas 299 cells. Such compounds are thus of interest for thetreatment of cancers, including solid tumors as well as lymphomas andincluding cancers which are resistant to other therapies.

Such cancers include, among others, cancers of the breast, non smallcell lung cancer (NSCLS), neural tumors such as glioblastomas andneuroblastomas; esophaegeal carcinomas, soft tissue cancers such asrhabdomyosarcomas, among others); various forms of lymphoma such as anon-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma(ALCL), various forms of leukemia; and including cancers which are ALKor c-met mediated.

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spannning receptortyrosine kinase, which belong to the insulin receptor subfamily. ALKreceptor tyrosine kinase (RTK) was initially identified due to itsinvolvement in the human non-Hodgkin lymphoma subtype known asanaplastic large-cell lymphoma (ALCL). ALK normally has a restricteddistribution in mammalian cells, being found at significant levels onlyin nervous system during embryonic development, suggesting a possiblerole for ALK in brain development (Duyster, J. Et al., Oncogene, 2001,20, 5623-5637).

In addition to its role in normal development, expression of thefull-length normal ALK has also been detected in cell lines derived froma variety of tumors such as neuroblastomas, neuroectodermal tumors(Lamant L. Et al., Am. J. Pathol., 2000, 156, 1711-1721;Osajima-Hakomori Y., et al., Am. J. Pathol. 2005, 167, 213-222) andglioblastoma (Powers C. et al., J. Biol. Chem. 2002, 277, 14153-14158;Grzelinski M. et al., Int. J. Cancer, 2005, 117, 942-951; Mentlein, R.Et al., J. Neurochem., 2002, 83, 747-753) as well as breast cancer andmelanoma lines (Dirk W G. Et al., Int. J. Cancer, 2002, 100, 49-56).

In common with other RTKs, translocations affect the ALK gene, resultingin expression of oncogenic fusion kinases-the most common of which isNPM-ALK. For example, approximately sixty percent of anaplastic largecell lymphomas (ALCL) are associated with a chromosome mutation thatgenerates a fusion protein consisting of nucleophosmin (NMP) and theintracellular domain of ALK. (Armitage, J. O. et al., Cancer: principleand practice of oncology, 6^(th) Edition, 2001, 2256-2316; kutok, J. L.& Aster J. C., J. Clin. Oncol., 2002, 20, 3691-3702; Wan, W. et al.,Blood, 2006, 107, 1617-1623. This mutant protein, NMP-ALK, possesses aconstitutively active tyrosine kinase domain that is responsible for itsoncogenic property through activation of downstream effectors (Falini, Band al., Blood, 1999, 94, 3509-3515; Morris, S. W. et al., Brit. J.Haematol., 2001, 113, 275-295). Experimental data have demonstrated thatthe aberrant expression of constitutuvely active ALK is directlyimplicated in the pathogenesis of ALCL and that inhibition of ALK canmarkedly impair the growth of ALK positive lymphoma cells (Kuefer, Mu etal., Blood, 1997, 90, 2901-2910; Bai, R. Y. et al., Exp. Hematol., 2001,29, 1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61, 2194-2199;Turturro, F. et al., Clin. Cancer. Res., 2002, 8, 240-245). Theconstitutively activated chimeric ALK has also been demonstrated inabout 60% of inflammatory myofibroblastic tumors (IMTs), a slow growingsarcoma that mainly affects children and young adults (Lawrence, B. etal., Am. J. Pathol., 2000, 157, 377-384). Furthermore, recent reportshave also described the occurrence of a variant ALK fusion, TPM4-ALK, incases of squamous cell carcinoma (SCC) of the esophagus (Jazzi fr., etal., World J. Gastroenterol., 2006, 12, 7104-7112; Du X., et al., J.Mol. Med., 2007, 85, 863-875; Aklilu M., Semin. Radiat. Oncol., 2007,17, 62-69). Thus, ALK is one of the few examples of an RTK implicated inoncogenesis in both non-hematopoietic and hematopoietic malignancies.More recently it has been shown that a small inversion within chromosome2p results in the formation of a fusion gene comprisinig portions of theechinoderm microtubule-associated protein-like 4 (EML4) gene and theanaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer(NSCLC) cells (Soda M., et al., Nature, 2007, 448, 561-567).

We therefore envision that an ALK inhibitor would either permit durablecures when used as a single therapeutic agent or combined with currentchemotherapy for ALCL, IMT, proliferative disorders, glioblastoma andother possible solid tumors cited herein, or, as a single therapeuticagent, could be used in a maintenance role to prevent recurrence inpatients in need of such a treatment.

Pharmaceutical Methods

The invention features methods for treating a subject having or at riskof contracting cancer by administering to the subject a therapeuticallyeffective amount of a compound of the invention.

A “therapeutically effective amount” is that amount effective fordetectable killing or inhibition of the growth or spread of cancercells; the size or number of tumors; or other measure of the level,stage, progression or severity of the cancer. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the disease, theparticular anticancer agent, its mode of administration, combinationtreatment with other therapies, and the like.

The compound, or a composition containing the compound, may beadministered using any amount and any route of administration effectivefor killing or inhibiting the growth of tumors or other forms of cancer.

The anticancer compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of anticancer agent appropriate for the patient to betreated. As is normally the case, the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician using routine reliance upon sound medical judgment. Thespecific therapeutically effective dose level for any particular patientor organism will depend upon a variety of factors including the disorderbeing treated; the severity of the disorder; the potency of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the route andschedule of administration; the rate of metabolism and/or excretion ofthe compound; the duration of the treatment; drugs used in combinationor coincident with administration of the compound of the invention; andlike factors well known in the medical arts.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the compositions of theinvention can be administered to humans and other animals orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by transdermal patch, powders,ointments, or drops), sublingually, bucally, as an oral or nasal spray,or the like.

The effective systemic dose of the compound will typically be in therange of 0.01 to 500 mg of compound per kg of patient body weight,preferably 0.1 to 125 mg/kg, and in some cases 1 to 25 mg/kg,administered in single or multiple doses. Generally, the compound may beadministered to patients in need of such treatment in a daily dose rangeof about 50 to about 2000 mg per patient. Administration may be once ormultiple times daily, weekly (or at some other multiple-day interval) oron an intermittent schedule. For example, the compound may beadministered one or more times per day on a weekly basis (e.g. everyMonday) indefinitely or for a period of weeks, e.g. 4-10 weeks.Alternatively, it may be administered daily for a period of days (e.g.2-10 days) followed by a period of days (e.g. 1-30 days) withoutadministration of the compound, with that cycle repeated indefinitely orfor a given number of repititions, e.g. 4-10 cycles. As an example, acompound of the invention may be administered daily for 5 days, thendiscontinued for 9 days, then administered daily for another 5 dayperiod, then discontinued for 9 days, and so on, repeating the cycleindefinitely, or for a total of 4-10 times.

The amount of compound which will be effective in the treatment orprevention of a particular disorder or condition will depend in part onwell known factors affecting drug dosage. In addition, in vitro or invivo assays may optionally be employed to help identify optimal dosageranges. A rough guide to effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.The precise dosage level should be determined by the attending physicianor other health care provider and will depend upon well known factors,including route of administration, and the age, body weight, sex andgeneral health of the individual; the nature, severity and clinicalstage of the disease; the use (or not) of concomitant therapies; and thenature and extent of genetic engineering of cells in the patient.

When administered for the treatment or inhibition of a particulardisease state or disorder, the effective dosage of the compound of theinvention may vary depending upon the particular compound utilized, themode of administration, the condition, and severity thereof, of thecondition being treated, as well as the various physical factors relatedto the individual being treated. In many cases, satisfactory results maybe obtained when the compound is administered in a daily dosage of fromabout 0.01 mg/kg-500 mg/kg, preferably between 0.1 and 125 mg/kg, andmore preferably between 1 and 25 mg/kg. The projected daily dosages areexpected to vary with route of administration. Thus, parenteral dosingwill often be at levels of roughly 10% to 20% of oral dosing levels.

When the compound of the invention is used as part of a combinationregimen, dosages of each of the components of the combination areadministered during a desired treatment period. The components of thecombination may administered at the same time; either as a unitarydosage form containing both components, or as separate dosage units; thecomponents of the combination can also be administered at differenttimes during a treatment period, or one may be administered as apretreatment for the other.

Regarding the Compounds

Compounds of present invention can exist in free form for treatment, orwhere appropriate, as a pharmaceutically acceptable salt, ester, orprodrug. As used herein, the term “pharmaceutically acceptable salt”refers to those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts of amines, carboxylic acids,phosphonates and other types of compounds, are well known in the art.For example, S. M. Berge, et al. describe pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977),incorporated herein by reference. The salts can be prepared in situduring the isolation and purification of compounds of the invention, orseparately by reacting the free base or free acid of a compound of theinvention with a suitable base or acid, respectively. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers preferably to esters which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Suitable ester groups include, for example,those derived from pharmaceutically acceptable aliphatic carboxylicacids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioicacids, in which each alkyl or alkenyl moiety advantageously has not morethan 6 carbon atoms. Examples of particular esters include formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.Obviously, esters can be formed with a hydroxyl or carboxylic acid groupof the compound of the invention.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of compounds of the invention. The term“prodrug” refers to compounds that are transformed in vivo to yield theparent compound of the above formula, for example by hydrolysis inblood. See, e.g., T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

Pharmaceutical Compositions

The invention also features pharmaceutical compositions including acompound of the invention, or a prodrug, pharmaceutically acceptablesalt or other pharmaceutically acceptable ester thereof, and one or morepharmaceutically acceptable carriers or excipients. The pharmaceuticalcompositions optionally further comprise one or more additionaltherapeutic agents. In certain instances a compound of the invention maybe administered to a subject undergoing one or more other therapeuticinterventions (e.g. Gleevec or other kinase inhibitors, interferon, bonemarrow transplant, farnesyl transferase inhibitors, bisphosphonates,thalidomide, cancer vaccines, hormonal therapy, antibodies, radiation,etc). For example, the compound of the invention can be used as onecomponent of a combination therapy in which one or more additionaltherapeutic agents (e.g., an anticancer agent), the agents being eitherformulated together or separately, is administered to the subject.

The pharmaceutical compositions of the invention include apharmaceutically acceptable carrier or excipient. Pharmaceuticallyacceptable carriers and excipient that can be used in the pharmaceuticalcompositions of the invention include, without limtiation, solvents,diluents, or other vehicle, dispersion or suspension aids, surfaceactive agents, isotonic agents, thickening or emulsifying agents,preservatives, solid binders, lubricants and the like, as suited to theparticular dosage form desired. Remington's Pharmaceutical Sciences,Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975)discloses various carriers used in formulating pharmaceuticalcompositions and known techniques for the preparation thereof. Someexamples of materials which can serve as pharmaceutically acceptablecarriers or excipients include, but are not limited to, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition.

Compounds of the invention may be administered by any suitable route,preferably in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment intended. Compounds ofthe invention may, for example, be administered orally, mucosally,topically, rectally, pulmonarily such as by inhalation spray, orparentally including intravascularly, intravenously, intraperitoneally,subcutaneously, intramuscularly, intrasternally and infusion techniques,in dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Each unitdosage may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more commonly from about 5 to 200mg. The amount of a compound of the invention to be administered willtypically be in the range of 0.01 to 500 mg of compound per kg bodyweight, preferably between 0.1 and 125 mg/kg body weight and in somecases between 1 and 25 mg/kg body weight. As mentioned previously, thedaily dose can be given in one administration or may be divided between2, 3, 4 or more administrations.

In the case of skin conditions, it may be preferable to apply a topicalpreparation of compounds of the invention to the affected area two tofour times a day. Formulations suitable for topical administrationinclude liquid or semi-liquid preparations suitable for penetrationthrough the skin (e.g., liniments, lotions, ointments, creams, orpastes) and drops suitable for administration to the eye, ear, or nose.A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at Least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs.

Compounds of the invention can also be administered by a transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent isdelivered—continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of the invention may be constituted fromknown ingredients in a known manner.

While the phase may comprise merely an emulsifier, it may comprise amixture of at least one emulsifier with a fat or an oil or with both afat and an oil. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the socalledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. Emulsifiers and emulsion stabilizers suitablefor use in the formulation of the invention include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired.

Alternatively, high melting point lipids such as white soft paraffinand/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients.

The active ingredients are preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% and particularlyabout 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers.

Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art. The active ingredient may also be administeredby injection as a composition with suitable carriers including saline,dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolventsolubilization (i.e. propylene glycol) or micellar solubilization (i.e.Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Combination Therapy

Compounds of the invention can be administered as part of a treatmentregimen in which the compound is the sole active pharmaceutical agent,or used in combination with one or more other therapeutic agents as partof a combination therapy. When administered as one component of a acombination therapy, the therapeutic agents being administered can beformulated as separate compositions that are administered at the sametime or sequentially at different times (e.g., within 72 hours, 48hours, or 24 hours of one another), or the therapeutic agents can beformulated together in a single pharmaceutical composition andadministered simultaneously.

Thus, the administration of compounds of the invention may be inconjunction with additional therapies known to those skilled in the artin the prevention or treatment of cancer, such as radiation therapy orcytostatic agents, cytotoxic agents, other anti-cancer agents and otherdrugs to ameliorate symptoms of the cancer or side effects of any of thedrugs.

If formulated as a fixed dose, such combination products employcompounds of the invention within the accepted dosage ranges. Compoundsof the invention may also be administered sequentially with otheranticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered prior to,simulateously with, or after administration of the other anticancer orcytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision, when appropriate, followed by either radiation orchemotherapy, and typically administered intravenously (IV). The typicalchemotherapy regime consists of either DNA alkylating agents, DNAintercalating agents, CDK inhibitors, or microtubule poisons. Thechemotherapy doses used are just below the maximal tolerated dose andtherefore dose limiting toxicities typically include, nausea, vomiting,diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of cancer by combination drug chemotherapy.And there are several major categories of such antineoplastic agents,namely, antibiotic-type agents, alkylating agents, antimetaboliteagents, hormonal agents, immunological agents, interferon-type agentsand a category of miscellaneous agents.

A first family of antineoplastic agents which may be used in combinationwith compounds of the invention includes antimetabolite-type/thymidilatesynthase inhibitor antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from but not limited to the groupconsisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole,brequinar sodium, carmofur, CibaGeigy CGP-30694, cyclopentyl cytosine,cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF,Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox,Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.

EX-015, fazarabine, floxuridine, fludarabine phosphate, 5fluorouracil,N-(21-furanidyl) fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the invention consists of alkylating-typeantineoplastic agents. Suitable alkylating-type antineoplastic agentsmay be selected from but not limited to the group consisting of Shionogi254-S, aldo-phosphamide analogues, altretamine, anaxirone, BoehringerMannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D 384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G M, Chinoin GYKI-17230, hepsulfam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactolf Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN II, Ajinomoto AN3, Nippon Sodaanisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-MyersBL-6859, Bristol-Myers BMY-25067, Bristol-Myers BNY-25551, Bristol-MyersBNY-26605 IBristolMyers BNY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko, DC89-Al, Kyowa Hakko DC92-B, ditrisarubicinB, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb,Erbamont FCE21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-1, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the invention consists of a miscellaneousfamily of antineoplastic agents, including tubulin interacting agents,topoisomerase II inhibitors, topoisomerase I inhibitors and hormonalagents, selected from but not limited to the group consisting of(xcarotene, (X-difluoromethyl-arginine, acitretin, Biotec AD-5, KyorinAHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat,ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1F Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, BristoMyers BNY-40481,Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773,caracemide, carmethizole hydrochloride, Ajinomoto CDAF,chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-LambertCI-921, WarnerLambert CI-937, Warner-Lambert CI-941, Warner-LambertCI958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711,Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B.cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine,datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, DaiichiSeiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, TsumuraEPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide,Fujisawa FR-57704t gallium nitrate, genkwadaphnin, Chugai GLA-43, GlaxoGR-63178, grifolan NMF5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU 1121 Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlnederivatives, methylanilinoacridine, Molecular Genetics MGI136,minactivin, mitonafide, mitoquidone mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, WarnerLambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-NI, interferon alfa-n3, interferonalfacon1, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-I beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama. vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinidel filgrastim SDO1 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypicCEA MAb (Trilex), LYM iodine 131 MAb (Techniclone), polymorphicepithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril,mitumomab, motexafin, gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN)y SU6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine,thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine(Biomira), melanoma vaccine (New York University), melanoma vaccine(Sloan Kettering Institute), melanoma oncolysate vaccine (New YorkMedical College), viral melanoma cell lysates vaccine (Royal NewcastleHospital), or valspodar.

Treatment Kits

In other embodiments, the invention relates to a kit for convenientlyand effectively carrying out the methods in accordance with theinvention. In general, the pharmaceutical pack or kit comprises one ormore containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention and instructions foradministering the pharmaceutical composition (e.g., a label or packageinsert) as part of a method described herein. Such kits are especiallysuited for the delivery of solid oral forms such as tablets or capsules.Such a kit preferably includes a number of unit dosages, and may alsoinclude a card having the dosages oriented in the order of theirintended use. If desired, a memory aid can be provided, for example inthe form of numbers, letters, or other markings or with a calendarinsert, designating the days in the treatment schedule in which thedosages can be administered. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticalproducts, which notice reflects approval by the agency of manufacture,use or sale for human administration.

The following representative examples contain important additionalinformation, exemplification and guidance which can be adapted to thepractice of the invention in its various embodiments and the equivalentsthereof. These examples are intended to help illustrate the invention,and are not intended to, nor should they be construed to, limit itsscope. Indeed, various modifications of the invention, and many furtherembodiments thereof, in addition to those shown and described herein,will become apparent to those skilled in the art upon review of thisdocument, including the examples which follow and the references to thescientific and patent literature cited herein. The contents of thosecited references are incorporated herein by reference to help illustratethe state of the art. In addition, for purposes of the invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “Organic Chemistry”, Morrison & Boyd (3dEd), the entire contents of both of which are incorporated herein byreference.

EXAMPLES Example 1N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine

4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine:A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol)in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine,was allowed to stirred at room temperature for 15 minutes until a clearsolution was obtained. 2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7g, 2.6 mmol) was added in four portions over 5 minutes. The reactionmixture was stirred at 60 degrees for 1 hour. The reaction mixture wascooled to room temperature and filtered to obtain a white solid. Thewhite solid was washed with 50 mL of water three times and followed by50 mL of Ethyl ether three times. The white solid was dried under vacuumto yield desired product (3.8 g, 49% yield). MS ES+: m/z=350.

N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine:To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(25 mg, 0.072 mmol) in 1.5 mL of ethanol was added 10 μL oftriethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixturewas microwave at 120 degrees for 20 minutes. The reaction mixture wasfiltered through a syringe filter and purified by prep-HPLC (WatersSunfire C18 column with ACN/water mobile phases) to yield a white solidas product (24 mg, 79% yield.) MS/ES+: m/z=414.

Example 2N²-[4-(dimethylphosphoryl)phenyl]-N⁴-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:27 mg, 0.078 mmol) in 1.5 mL of ethanol wasadded 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol).The mixture was microwave at 120 degrees for 20 minutes. The reactionmixture was filtered through a syringe filter and purified by prep-HPLC(Waters Sunfire C18 column with ACN/water mobile phases) to yield awhite solid as product (3 mg, 8% yield.) MS/ES+: m/z=465.

Example 4N²-[4-(dimethylphosphoryl)phenyl]-N²-(morpholin-4-ylmethyl)-5(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of ethanol was added50 μL of triethylamine and 4-(2-aminoethyl) morpholine (15 mg, 0.12mmol). The mixture was microwave at 120 degrees for 20 minutes. Thereaction mixture was filtered through a syringe filter and purified byprep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield a white solid as product (42 mg, 81% yield.) MS/ES+: m/z=430.

Example 54-(2-{[2-{[4-(dimethylphosphoryl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}ethyl)benzenesulfonamide

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of ethanol was added50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg,0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. Thereaction mixture was filtered through a syringe filter and purified byprep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield a white solid as product (30 mg, 49% yield.) MS/ES+: m/z=514.

Example 6N²-[4-(dimethylphosphoryl)phenyl]-N⁴-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of ethanol was added50 μL of triethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt(14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20minutes. The reaction mixture was filtered through a syringe filter andpurified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobilephases) to yield a white solid as product (27 mg, 59% yield.) MS/ES+:m/z=401.

Example 7N²-_([)4-(dimethylphosphoryl)phenyl]-N⁴-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of ethanol was added50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0] octanehydrochloride salt (19 mg, 0.12 mmol). The mixture was microwave at 120degrees for 20 minutes. The reaction mixture was filtered through asyringe filter and purified by prep-HPLC (Waters Sunfire C18 column withACN/water mobile phases) to yield a white solid as product (34 mg, 67%yield.) MS/ES+: m/z=440.

Example 8N²-[4-(dimethylphosphoryl)phenyl]-N⁴-(morpholin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 50 μIL of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol).The mixture was microwave at 120 degrees for 20 minutes. The reactionmixture was filtered through a syringe filter and purified by prep-HPLC(Waters Sunfire C18 column with ACN/water mobile phases) to yield awhite solid as product (6 mg, 12% yield.) MS/ES+: m/z=416.

Example 9N-[4-(dimethylphosphoryl)phenyl]-4-(4-phenylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of ethanol was added50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). Themixture was microwave at 120 degrees for 20 minutes. The reactionmixture was filtered through a syringe filter and purified by prep-HPLC(Waters Sunfire C18 column with ACN/water mobile phases) to yield awhite solid as product (40 mg, 73% yield.) MS/ES+: m/z=476.

Example 10N²-[4-(dimethylphosphoryl)phenyl]-N⁴-[2-(1H-indol-3-yl)ethyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 50 μL of triethylamine and Tryptamine (18 mg, 0.12 mmol). Themixture was microwave at 120 degrees for 20 minutes. The reactionmixture was filtered through a syringe filter and purified by prep-HPLC(Waters Sunfire C18 column with ACN/water mobile phases) to yield awhite solid as product (44 mg, 81% yield.) MS/ES+: m/z=474.

Example 11N²-[4-(dimethylphosphoryl)phenyl]-N⁴-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 50 μL of triethylamine and 1-Amino-4-methyl-piperazine (13 mg,0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. Thereaction mixture was filtered through a syringe filter and purified byprep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield a white solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.

Example 12N²-[4-(dimethylphosphoryl)phenyl]-N⁴-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-(trilluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 50 μL of triethylamine and 1-Adamantanemethylamine (19 mg, 0.12mmol). The mixture was microwave at 120 degrees for 20 minutes. Thereaction mixture was filtered through a syringe filter and purified byprep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=479

Example 13N²-[4-(dimethylphosphoryl)phenyl]-N⁴-[4-(4-methylpiperazin-1-yl)benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 50 μL of triethylamine and 4-(4-methylpiperazine)-benzylamine (24mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes.The reaction mixture was filtered through a syringe filter and purifiedby prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield a white solid as product (21 mg, 73% yield.) MS/ES+: m/z=519

Example 14N²-(3,5-dimethylphenyl)-N²-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine(prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol wasadded 10 μL of Hydrochloric acid in Methanol (2M) and 3,5-Dimethylaniline (14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for20 minutes. The reaction mixture was filtered through a syringe filterand purified by prep-HPLC (Waters Sunfire C18 column with ACN/watermobile phases) to yield a white solid as product (32 mg, 65% yield.)MS/ES+: m/z=435

Example 155-chloro-N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-phenylpyrimidine-2,4-diamine

2,5-dichloro-N-phenylpyrimidin-4-amine: To a solution of Aniline (205mg, 2.2 mmol) and 2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mLof Ethanol, was added 500 mg of Potassium carbonate. The reactionmixture was stirred at room temperature for 2 hours. Solvent was removedunder reduced pressure. The residue was purified by silica gel flashchromatography with 10% Ethyl Acetate in Heptane to yield the desiredproduct as an oil (370 mg, 70% yield).

(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide: To a solution of5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was addeddimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg,0.13 mmol), XANPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C.for 18 h. The reaction mixture was basified with saturated sodiumbicarbonate solution, and extracted with ethyl acetate. The organiclayer was concentrated and purified by prep-HPLC to give the finalproduct (0.16 g, 30% yield). MS/ES+: m/z=229.

4-(dimethylphosphoryl))-2-methoxyaniline: To a solution of(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) in5 mL of EtOH was added 10% weight of palladium on carbon (0.2 g). Themixture was purged with argon, and hydrogenated under 30 psi for 2 h.The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.088 g,86% yield). MS/ES+: m/z=199.

5-chloro-N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-phenylpyrimidine-2,4-diamine:To a solution of 2,5-dichloro-N-phenylpyrimidin-4-amine (84 mg, 0.35mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in1 mL of DMF, was added 0.36 mL of 2.5M HCl in Ethanol. The reactionmixture was heated in a sealed tube at 140 degrees over night. Thereaction mixture was filtered through a syringe filter and purified byPrep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) toyield the desired product as a white solid. (23 mg, 16% yield). MS/ES+:m/z=403

Example 16N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine:To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, was added Sodiumhydride (100 mg) and the reaction mixture was allowed to stirred at 0degree for 20 minutes. 2,4-Dichloro-5-(trifluoromethyl) pyrimidine (350mg, 1.6 mmol) was added in one portion and the reaction mixture waswarmed to room temperature. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water andextracted with Ethyl acetate. The combined Ethyl acetate layers weredried over Sodium Sulfate and solvent was removed under reducedpressure. The residue was purified by Prep-HPLC to yield the desiredproduct as a white solid (10 mg, 2% yield).

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine:To a solution of2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine(7.5 mg, 0.02 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline(prepared as in Example 15: 15 mg, 0.7 mmol) in 1 mL of 2-Methoxyethanol, was added 1 mL of 2.5M HCl in Ethanol. The reaction mixture washeated in a sealed tube at 140 degree over night. The reaction mixturewas filtered through a syringe filter and purified by Prep-HPLC (WatersSunfire C18 column with ACN/water mobile phases) to yield the desiredproduct as a white solid. (0.9 mg, 8% yield). MS/ES+: m/z=543

Example 175-chloro-N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine: To asolution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol)in 2 mL of DMF at 0° C. was added NaH (60% in oil, 0.349 g, 8.72 mmol)in one portion. After stirring fro 20min, 2,4,5-trichloropyrimidine wasadded. The mixture was stirred at 0° C. for 30 minutes, and then at roomtemperature for 2 h. After quenching with saturated ammonium chloridesolution, the mixture was poured in water and ethyl acetate mixture.Yellow suspension was filtered as final product (0.3 g, 20% yield).MS/ES+: m/z=346.

5-chloro-N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.050g, 0.14 mmol) in 1 mL of 2-methoxyethanol was added4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 15:0.029 g, 0.14 mmol) and 0.12 ml of 2.5M HCl in EtOH. The mixture washeated in a sealed tube at 140° C. for 1 h. The mixture was basifiedwith saturated sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was purified by prep-HPLC to give the finalproduct (20 mg, 24% yield). MS/ES+: m/z=508.

Example 185-chloro-N²-[4-(dimethylphosphoryl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(prepared as in Example 17: 50 mg, 0.14 mmol) in 1 mL of2-methoxyethanol was added 4-(dimethylphosphoryl)-2-methoxyaniline(prepared as in Example 15: 0.025 g, 0.14 mmol) and 0.12 ml of 2.5M HClin EtOH. The mixture was heated in a sealed tube at 140° C. for 1 h. Themixture was basified with saturated sodium bicarbonate solution, andextracted with ethyl acetate. The organic layer was purified byprep-HPLC to give the final product (0.100 g, 15% yield). MS/ES+:m/z=478.

Example 195-chloro-N⁴-[4-(dimethylphosphoryl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine: To asolution of 2,4,5-trichloropyrimindine (0.15 ml, 1.31 mmol) in 1 mL ofDMF was added 4-(dimethylphosphoryl)aniline (0.221 g, 1.31 mmol) andpotassium carbonate (0.217 g, 1.57 mmol). The mixture was heated at 110°C. for 4 h. It was basified with saturated sodium bicarbonate solution.The suspension was filtered and washed with ethyl acetate to give thefinal product (0.15 g, 36% yield). MS/ES+: m/z=316.

1-[1-(3-methoxy-4-nitrophenl)piperidin-4-yl]-4-methylpiperazine: To asolution of 5-fluoro-2-nitroanisoole (0.5 g, 2.92 mmol) in 3 mL of DMFwas added 1-methyl-4-(piperidin)piperazine (0.536 g, 2.92 mmol) andpotassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120°C. for 18 h. The mixture was basified with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer waspurified by chromatography to give final product as yellow solid (0.95g, 95% yield). MS/ES+: m/z=334.

2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline: The asolution of1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g,0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladiumon carbon (0.060 g). The hydrogenation was finished under 30 psi after 4h. The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.15 g,88% yield). MS/ES+: m/z=334.

5-chloro-N⁴-[4-(dimethylphosphoryl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine:To the compound2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.005 g,0.16 mmol) in 1 mL of 2-methoxyethanol was added2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g,0.16 mmol). The mixture was stirred at 110° C. for 18 h. The mixture wasbasified with saturated sodium bicarbonate solution and extracted withlimited amount of ethyl acetate. The aqueous layer was purified bychromatography to give the final product (0.015 g, 20% yield). MS/ES+:m/z=583.

Example 20N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine: To asuspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in2.0 mL of DMF at room temperature was added1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3portions. After 30 minutes of stirring at room temperature,2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution in 1.0mL DMF. The reaction mixture stirred for 3 h at room temperature. Thereaction was quenched with saturated sodium bicarbonate solution and thesolution extracted ethyl acetate. The organic layers were combined,washed with saturated sodium chloride solution, dried with sodiumsulfate, filtered and concentrated. The crude residue was purified bysilica gel chromatography (0-30% ethyl acetate:heptane) to afford thedesired compound as an off-white solid (53 mg, 17% yield). MS/ES+:m/z=312.

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.017 g,0.054 mmol) in 0.5 mL of 2-methoxyethanol in a vial was added4-(dimethylphosphoryl)-2-methyoxyaniline (0.010 g, 0.044 mmol) as theHCl salt. The vial was sealed and the reaction was heated at 90° C. for16 h. The reaction was quenched with 1N NaOH solution and the solutionextracted ethyl acetate. The organic layers were combined, washed withsaturated sodium chloride solution, dried with sodium sulfate, filteredand concentrated. The crude residue was purified by silica gelchromatography (0-10% 7N ammonia in methanol:dichloromethane) to affordthe desired compound (15 mg, 72% yield). MS/ES+: m/z=475.

Example 21N²-[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine:To a suspension of NaH (60% dispersion in mineral oil, 40.0 mg, 1.00mmol) in 2 mL of DMF at room temperature was added1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3portions. After 30 minutes of stirring at room temperature,2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added as asolution in 1 mL DMF. The reaction mixture stirred for 3 h at roomtemperature. The reaction was quenched with saturated sodium bicarbonatesolution and the solution extracted ethyl acetate. The organic layerswere combined, washed with saturated sodium chloride solution, driedwith sodium sulfate, filtered and concentrated. The crude residue waspurified by silica gel chromatography (0-30% ethyl acetate:heptane) toafford the desired compound as an off-white solid (78 mg, 24% yield).MS/ES+: m/z=326.

N²-[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine(0.035 g, 0.11 mmol) in 1 mL of 2-methoxyethanol in a vial was added4-(dimethylphosphoryl)-2-methyoxyaniline (0.020 g, 0.085 mmol) as theHCl salt. The vial was sealed and the reaction was heated at 90° C. for16 h. The reaction was quenched with 1N NaOH solution and the solutionextracted ethyl acetate. The organic layers were combined, washed withsaturated sodium chloride solution, dried with sodium sulfate, filteredand concentrated. The crude residue was purified by silica gelchromatography (0-10% 7N ammonia in methanol:dichloromethane) to affordthe desired compound (12 mg, 29% yield). MS/ES₊: m/z=489.

Example 225-Chloro-N²-[5-(dimethylphosphoryl)-2-methoxyphenyl]-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

5-(Dimethylphosphoryl)-2-methoxyaniline: To a solution of5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.365 g, 85% yield).

5-Chloro-N²-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (asprepared in Example 17: 0.077 g, 0.22 mmol) in 1.5 mL of2-methoxyethanol was added 5-(dimethylphosphoryl)-2-methoxyaniline(0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was heatedin a sealed tube at 90° C. for 16 h. The mixture was basified with 1NNaOH solution, and extracted with ethyl acetate. The organic layers werecombined, washed with saturated sodium chloride solution, dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by prep-HPLC to afford the final compound (52 mg, 48% yield).MS/ES+: m/z=509.

Example 235-Chloro-N²-[4-(dimethylphosphoryl)-2-methylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

4-(Dimethylphosphoryl)-2-methylaniline: To a solution of4-bromo-2-methylaniline (0.372 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.313 g, 85% yield).

5-Chloro-N²-[4-(dimethylphosphoryl)-2-methylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (asprepared in Example 17: 0.083 g, 0.24 mmol) in 1.5 mL of2-methoxyethanol was added 4-(dimethylphosphoryl)-2-methylaniline (0.050g, 0.23 mmol) as its hydrochloride salt. The mixture was heated in asealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOHsolution, and extracted with ethyl acetate. The organic layers werecombined, washed with saturated sodium chloride solution, dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by prep-HPLC to afford the final compound (20 mg, 18% yield).MS/ES+: m/z=493.

Example 245-Chloro-N²-[4-(dimethylphosphoryl)-2-ethylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

4-(Dimethylphosphoryl)-2-ethylaniline: To a solution of4-bromo-2-ethylaniline (0.400 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.308 g, 78% yield).

5-Chloro-N²-[4-(dimethylphosphoryl)-2-ethylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (asprepared in Example 17: 0.079 g, 0.22 mmol) in 1.5 mL of2-methoxyethanol was added 4-(dimethylphosphoryl)-2-ethylaniline (0.050g, 0.21 mmol) as its hydrochloride salt. The mixture was heated in asealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOHsolution, and extracted with ethyl acetate. The organic layers werecombined, washed with saturated sodium chloride solution, dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by prep-HPLC to afford the final compound (43 mg, 40% yield).MS/ES+: m/z=507.

Example 255-Chloro-N²-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline: To a solution of4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF wasadded dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate(22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl inmethanol to afford the desired product as its hydrochloride salt (0.573g, 98% yield).

5-Chloro-N²-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (asprepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanolwas added 4-(dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.035 g,0.12 mmol) as its hydrochloride salt. The mixture was heated in a sealedtube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution,and extracted with ethyl acetate. The organic layers were combined,washed with saturated sodium chloride solution, dried with sodiumsulfate, filtered and concentrated. The crude residue was purified byprep-HPLC to afford the final compound (5.8 mg, 9% yield). MS/ES+:m/z=563.

Example 265-Chloro-N²-[2-chloro-4-(dimethylphosphoryl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

2-Chloro-4-(dimethylphosphoryl)aniline: To a solution of2-chloro-4-iodoaniline (0.507 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.340 g, 83% yield).

5-Chloro-N²-[2-chloro-4-(dimethylphosphoryl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.040g, 0.12 mmol) in 1 mL of 2-methoxyethanol was added2-chloro-4-(dimethylphosphoryl)aniline (as prepared in Example 17: 0.025g, 0.12 mmol) and 49 μL of 2.5 M HCl in ethanol. The mixture was heatedin a sealed tube at 90° C. for 16 h. The mixture was basified with 1NNaOH solution, and extracted with ethyl acetate. The organic layers werecombined, washed with saturated sodium chloride solution, dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by prep-HPLC to afford the final compound (5.9 mg, 10% yield).MS/ES+: m/z=513.

Example 275-Chloro-N²-[4-(dimethylphosphoryl)-2-fluorophenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

4-(Dimethylphosphoryl)-2-fluoroaniline: To a solution of4-bromo-2-fluoroaniline (0.380 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (73.5 mg, 20% yield).

5-Chloro-N²-[1-(dimethylphosphoryl)-2-fluorophenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (asprepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanolwas added 4-(dimethylphosphoryl)-2-fluoroaniline (0.023 g, 0.12 mmol)and 49 μL of 2.5 M HCl in ethanol. The mixture was heated in a sealedtube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution,and extracted with ethyl acetate. The organic layers were combined,washed with saturated sodium chloride solution, dried with sodiumsulfate, filtered and concentrated. The crude residue was purified byprep-HPLC to afford the final compound (9.0 mg, 22% yield). MS/ES+:m/z=497.

Example 28N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine

A suspension ofN²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-nitro-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine(461 mg, 0.89 mmol) in Ethanol was added 184 mg of 10% Pd on carbon. Thereaction mixture was stirred at room temperature overnight and filteredthrough celite. The filtrate was concentrated under reduced pressure toyield the crude product. The crude product was purified by silica gelchromatography with 10% Methanol in DCM to yieldN²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamineas a solid. MS ES+: m/z=490.

Example 292-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}-9-[2-(propan-2-ylsulfonyl)phenyl]-7,9-dihydro-8H-purin-8-one

To a solution ofN²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine(as prepared in Example 28: 40 mg, 0.082 mmol) in THF was addedN,N′-Carbonyldiimidazole (40 mg, 0.25 mmol). The solution was stirred atroom temperature overnight. The solution was concentrated under reducedpressure and diluted with water and extracted with Ethyl Acetate. Thecombined organic layer was washed with brine and dried over MagnesiumSulfate. The organic layer was concentrated under reduced pressure andthe residue was purified by RP Prep-HPLC to obtain the desired productas an off white solid. MS/ES+: m/z=516

Example 30N²-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide: To a solution of5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was addeddiethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27mmol), XantPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g,5.86 mmol). The mixture was purged with nitrogen, and subjected tomicrowaves at 150° C. for 20 minutes. The reaction mixture wasconcentrated and purified by silica gel chromatography (0-45% ethylacetate:heptane) to afford the desired product (0.504 g, 33% yield).

(3-methoxy-4-nitrophenyl)phosphonic dichloride: To a solution of(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (4.54 g, 15.7 mmol)in 1.2 mL DMF was added thionyl chloride (5.7 mL, 78.5 mmol). Thereaction flask was equipped with a reflux condenser and the mixture washeated to reflux. After 2 h at reflux, the reaction was cooled to rt andconcentrated in vacuo. The crude oil was redissolved in CH₂Cl₂ andheptane was added to precipitate the desired compound. The clearsolution was decanted and the precipitate was collected and dried driedto afford the desired compound as a white solid (1.39 g, 33% yield).

Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide: To a solution of(3-methoxy-4-nitrophenyl)phosphonic dichloride (1.39 g, 5.15 mmol) in 15mL THF at −78° C. under nitrogen was slowly added vinylmagnesium bromide(10.3 mL, 1.0 M in THF). After the addition was complete, the reactionstirred at −78° C. for an additional hour. The cold reaction mixture wasquenched by the addition of saturated NH₄Cl (20 mL) and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed with 1 MNaOH, brine, and dried over MgSO₄. The organic extracts were filteredand concentrated to provide the desired compound (0.982 g, 75%).

1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide:diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.90 mmol)and benzylamine (0.23 mL, 2.08 mmol) were dissolved in 50% aqueous THF(6 mL) and heated to 105° C. under nitrogen. After one hour, anotherportion of benzylamine was added to the reaction mixture. The reactionmixture was refluxed for an additional 2 h, and then cooled to rt. Thereaction mixture was partitioned between saturated aqueous NaHCO₃ andCH₂Cl₂. The aqueous phase was washed once with CH₂Cl₂ and the organiclayers were combined. The organic extracts were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane)to afford the desired product (0.449 g, 66% yield).

4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline: To asolution of 1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane4-oxide (0.224 g, 0.622 mmol) in 0.6 mL 4:1 ethanol:water was added ironpowder (0.348 g, 6.22 mmol) and 0.30 mL ethanolic HCl (2.5 M). Thereaction vessel was sealed and was heated to 95° C. for 1 h. Thereaction mixture was cooled to rt, filtered, and concentrated. The cruderesidue was purified by silica gel chromatography (0-5% 7N ammonia inmethanol:dichloromethane) to afford the desired product (86.1 mg, 42%yield).

N²-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (47.3mg, 0.137 mmol) in 1.5 mL of 2-methoxyethanol was added4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (43.0 mg,0.13 mmol) and ethanolic HCl (0.10 mL, 2.5 M). The mixture was heated ina sealed vial at 90° C. for 16 h. The reaction was then heated at 100°C. for an additional 2 h. The mixture was basified with 1N NaOHsolution, and extracted with ethyl acetate. The organic layers werecombined, washed with saturated sodium chloride solution, dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by silica gel chromatography (0-12% 7N ammonia inmethanol:dichloromethane) to afford the desired product (43.0 mg, 52%yield).

N²-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:A flask was charged withN²-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (40.0 mg, 0.0625 mmol) and 10% Pd—C (40.0 mg).The flask was evacuated and filled with nitrogen. Anhydrous methanol (2mL) was added to the flask and the flask was equipped with a refluxcondenser with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500 mmol)was added in one portion at room temperature. The resulting mixture wasstirred at reflux for 3 h. The reaction was filtered through a Celitepad and the Celite was washed with 2×5 mL methanol. The combinedfiltrate and washing was evaporated in vacuo. The crude residue waspurified by prep-HPLC to afford the final compound (13.6 mg, 42% yield).MS/ES+: m/z=516.

Example 31N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine:To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in DMF (5mL) wasadded 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) at 0°C. The resulting mixture was stirred for 30 min before2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL, 1.1 eq) was added. Themixture was then warmed up to room temperature and stirred for 1 hr.Water was added to quench the reaction. Extraction with CH2Cl2 followedby drying combined organic layers, evaporation, and chromatography onsilica gel (20% EtOAc in heptane as eleunt) gave the desired product in84% yield (570 mg).

2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine:To a solution of 1-amino-2-(isopropylsulphonyl)benzene (199 mg, 1 mmol)in 2 mL of DMF was added NaH (60% in oil, 44 mg, 1.1 mmol) in oneportion at 0° C. After the reaction mixture was stirred for 20 min,2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine(317 mg, 1 mmol) was added at 0° C. The reaction mixture was then warmedup to room temperature and stirred for additional 2 h. The reaction wasquenched with water. Extraction with EtOAc followed by silica gel columnchromatography (20% EtOAc in heptane) gave the desired product (202 mg,42% yield). MS/ES+: m/z=481.

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine:To a microwave reaction tube was charged with2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(180 mg, 0.374 mmol), 4-(dimethylphosphonyl)-2-methoxyanilinehydrochloride (105 mg, 0.45 mmol), Pd2(dba)3 (34 mg, 0.0374 mmol),Xanthphos (26 mg, 0.045 mmol), and t-BuONa (129 mg, 1.346 mmol). Thismixture was degassed via 3-cycle of vacuum and re-fill with N2.Anhydrous 1,4-dioxane (2mL from sure-seal bottle) was added and thereaction was then run under microwave irradiation at 140° C. for 20 min.Water and EtOAc was added to facilitate extraction. Chromatography onsilica gel (10% MeOH in CH2Cl2 as eleunt) gave the desired product in54% yield (130 mg). MS/ES+: m/z=644.

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine:To a solution of compoundN²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diaminein THF (1 mL) was added tetrabutylammonium fluoride (TBAF) in THF (1.0M, 3 mL) and ethylenediamine (0.1 mL). The solution was heated at 60° C.for 24 hrs. About 40% conversion was observed by HPLC monitoring.Volatile components were removed on rotavap and the residue wassubjected to prep-HPLC purification. The desired product was determinedby NMR to be contaminated with TBAF, which was removed by water wash (4times). Evaporation of EtOAc gave the pure compound(14 mg). MS/ES+:m/z=514.

Example 325-chloro-N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine: To a solution of6-bromo-2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (77.2 mg, 39% yield).

2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine: To asolution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol)in 2 mL of DMF at 0° C. was added NaH (60% in oil, 0.349 g, 8.72 mmol)in one portion. After stirring fro 20 min, 2,4,5-trichloropyrimidine wasadded. The mixture was stirred at 0° C. for 30 minutes, and then at roomtemperature for 2 h. After quenching with saturated ammonium chloridesolution, the mixture was poured in water and ethyl acetate mixture.Yellow suspension was filtered as final product (0.3 g, 20% yield).MS/ES+: m/z=346.

5-chloro-N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (86.0mg, 0.250 mmol) in 1 mL of 2-methoxyethanol was added6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol)and 0.15 mL of 2.5 M HCl in ethanol. The mixture was heated in a sealedtube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution,and extracted with ethyl acetate. The organic layers were combined,washed with saturated sodium chloride solution, dried with sodiumsulfate, filtered and concentrated. The crude residue was purified bysilica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane)to afford the desired product (16.7 mg, 22% yield). MS/ES+: m/z=510.

Example 335-chloro-N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine: To a solution of5-bromo-3-methoxypyrazin-3-ylamine (0.204 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (126 mg, 63% yield).

5-chloro-N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a mixture of2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(prepared in Example 32: 0.120 g, 0.348 mmol) and5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348 mmol)was added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct(17.6 mg, 0.017 mmol), XANTPHOS (23.3 mg, 0.040 mmol), and cesiumcarbonate (0.228 g, 0.700 mmol), and dioxane (3.5 mL). The mixture wassealed and heated at 120° C. After 16 h, the reaction mixture was cooledto rt and concentrated. The crude residue was purified by silica gelchromatography (0-10% 7N ammonia in methanol:dichloromethane) to affordthe desired product (11.4 mg, 6% yield). MS/ES+: m/z=511.

Example 345-chloro-N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-phenylpyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2,5-dichloro-N-phenylpyrimidin-4-amine with6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example32)

2,5-dichloro-N-phenylpyrimidin-4-amine: To a solution of Aniline (205mg, 2.2 mmol) and 2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mLof Ethanol, was added 500 mg of Potassium carbonate. The reactionmixture was stirred at room temperature for 2 hours. Solvent was removedunder reduced pressure. The residue was purified by silica gel flashchromatography with 10% Ethyl Acetate in Heptane to yield the desiredproduct as an oil (370 mg, 70% yield).

Example 35N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine: A suspension of6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example32: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL ofDiisopropylethylamine, is allowed to stirred at room temperature for 15minutes until a clear solution is obtained.2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7 g, 2.6 mmol) is addedin four portions over 5 minutes. The reaction mixture is stirred at 60degrees for 1 hour. The reaction mixture is cooled to room temperatureand filtered to obtain a white solid. The white solid is washed with 50mL of water three times and followed by 50 mL of Ethyl ether threetimes. The white solid is dried under vacuum to yield4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine.

N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine:To a solution of4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine (0.072 mmol) in 1.5 mL of ethanol is added 10 μL oftriethylamine and 1-Amino-2-(isopropylsulphonyl)benzene (0.072 mmol).The mixture is microwave at 120 degrees for 20 minutes. The reactionmixture is filtered through a syringe filter and purified by prep-HPLC(Waters Sunfire C18 column with ACN/water mobile phases) to generate thedesired compound.

Example 36N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine:A suspension of 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine(prepared in Example 33: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and3.6 mL of Diisopropylethylamine, is allowed to stirred at roomtemperature for 15 minutes until a clear solution is obtained.2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7 g, 2.6 mmol) is addedin four portions over 5 minutes. The reaction mixture is stirred at 60degrees for 1 hour. The reaction mixture is cooled to room temperatureand filtered to obtain a white solid. The white solid is washed with 50mL of water three times and followed by 50 mL of Ethyl ether threetimes. The white solid is dried under vacuum to yield4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine.

N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine:Toa solution of4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine(0.072 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and1-Amino-2-(isopropylsulphonyl)benzene (0.072 mmol). The mixture ismicrowave at 120 degrees for 20 minutes. The reaction mixture isfiltered through a syringe filter and purified by prep-HPLC (WatersSunfire C18 column with ACN/water mobile phases) to generate the desiredcompound.

Example 375-chloro-N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-[4-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with2,6-Dimethoxypyridin-3-amine.

2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine: To asolution of 2,4,5-trichloropyrimidine (0.15 ml, 1.31 mmol) in 1 mL ofDMF was added 4-(dimethylphosphoryl)aniline (0.221 g, 1.31 mmol) andpotassium carbonate (0.217 g, 1.57 mmol). The mixture was heated at 110°C. for 4 h. It was basified with saturated sodium bicarbonate solution.The suspension was filtered and washed with ethyl acetate to give thefinal product (0.15 g, 36% yield). MS/ES+: m/z=316.

Example 385-chloro-N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline with2,4,5-trichloropyrimidine to generate2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine.2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amineis then reacted with 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine(prepared in Example 33) according to the procedure described in Example32.

1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine: To asolution of 5-fluoro-2-nitroanisoole (0.5 g, 2.92 mmol) in 3 mL of DMFwas added 1-methyl-4-(piperidin)piperazine (0.536 g, 2.92 mmol) andpotassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120°C. for 18 h. The mixture was basified with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer waspurified by chromatography to give final product as yellow solid (0.95g, 95% yield). MS/ES+: m/z=334.

2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline: The asolution of1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g,0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladiumon carbon (0.060 g). The hydrogenation was finished under 30 psi after 4h. The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.15 g,88% yield). MS/ES+: m/z=334.

Example 395-chloro-N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

This compound can be prepared by reacting 2,4,5-trichloropyrimidine with1-Methyl piperazine as described in Example 32 to generate2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine.2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine is then reacted with6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example32) as described in Example 32.

Example 40N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-(morpholin-4-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

This compound can be prepared by reacting 1-(morpholin-4-yl)methaneaminewith4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine as described in Example 35.

Example 414-(2-{[2-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}ethyl)benzenesulfonamide

This compound can be prepared by reacting4-(2-aminoethyl)benzene-sulfonamide with4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine as described in Example 35.

Example 422-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-4-(4-phenylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine

This compound can be prepared by reacting 1-Phenylpiperazine with4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidineas described in Example 36.

Example 432-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N-[2-(1H-indol-3-yl)ethyl]-5-(trifluoromethyl)pyrimidin-4-amine

This compound can be prepared by reacting tryptamine with4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidineas described in Example 36.

Example 44N²-[4-(dimethylphosphoryl)phenyl]-N⁴-[4-(4-methylpiperazin-1-yl)benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

This compound can be prepared by reacting4-(4-methylpiperazine)-benzylamine with4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidineas described in Example 36.

Example 45N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine with6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example32).

2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine: To asuspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in2.0 mL of DMF at room temperature was added1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3portions. After 30 minutes of stirring at room temperature,2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution in 1.0mL DMF. The reaction mixture stirred for 3 h at room temperature. Thereaction was quenched with saturated sodium bicarbonate solution and thesolution extracted ethyl acetate. The organic layers were combined,washed with saturated sodium chloride solution, dried with sodiumsulfate, filtered and concentrated. The crude residue was purified bysilica gel chromatography (0-30% ethyl acetate:heptane) to afford thedesired compound as an off-white solid (53 mg, 17% yield). MS/ES+:m/z=312.

Example 46N²-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2-Chloro-5-methyl-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-aminewith 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared inExample 32).

2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine:To a suspension of NaH (60% dispersion in mineral oil, 40.0 mg, 1.00mmol) in 2 mL of DMF at room temperature was added1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3portions. After 30 minutes of stirring at room temperature,2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added as asolution in 1 mL DMF. The reaction mixture stirred for 3 h at roomtemperature. The reaction was quenched with saturated sodium bicarbonatesolution and the solution extracted ethyl acetate. The organic layerswere combined, washed with saturated sodium chloride solution, driedwith sodium sulfate, filtered and concentrated. The crude residue waspurified by silica gel chromatography (0-30% ethyl acetate:heptane) toafford the desired compound as an off-white solid (78 mg, 24% yield).MS/ES+: m/z=326.

Example 475-chloro-N⁴-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N²-(thiophen-2-ylmethyl)pyrimidine-2,4-diamine

The compound can be prepared as in Example 32 by reacting2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline with2,4,5-trichloropyrimidine generating2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine.2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amineis then reacted with 1-(thiophen-2-yl)methanamine as described inExample 32.

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline

1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide: To a solution ofmethylphosphonic dischloride (10.0 g, 75.2 mmol) in CH₂Cl₂ at −78° C.,was added vinylmagnesium bromide (175 mL, 1.0 M in THF) via additionfunnel over 4 h. The solution was warmed to 0° C. and quenched with aminimum amount of saturated NH₄Cl. The mixture was filtered through apad of silica gel and silica was extracted with 10% 7N ammonia inmethanol:dichloromethane. The solution was concentrated under reducedpressure to afford methyl divinyl phosphine oxide as a viscous, yellowoil that was used without purification.

A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) andbenzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated atreflux for 16 h. The reaction mixture was concentrated in vacuo and theresidue was purified by silica gel chromatography (0-10% 7N ammonia inmethanol:dichloromethane) to afford1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g,70% yield).

4-methyl-[1,4]azaphosphinane-4-oxide: A flask was charged with1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol) and10% Pd/C (100 mg). The flask was evacuated and filled with nitrogen.Anhydrous methanol (18 mL) was added to the flask and the flask wasequipped with a reflux condenser with a nitrogen inlet. Ammonium formate(2.25 g, 35.8 mmol) was added in one portion at room temperature. Theresulting mixture was stirred at reflux for 2 h. The reaction wasfiltered through a Celite pad and the Celite was washed with 2×5 mLmethanol. The combined filtrate and washing was evaporated in vacuo. Thecrude residue was purified by silica gel chromatography (0-10% 7Nammonia in methanol:dichloromethane) to afford4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%yield).

1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide: Amixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol),5-fluoro-2-nitroanisole (340 mg, 2.00 mmol), K₂CO₃ (345 mg, 2.50 mmol),and DMF (5 mL) was heated to 50° C. After 2 h, the reaction mixture wasconcentrated and purified by silica gel chromatography (0-5% 7N ammoniain methanol:dichloromethane) to afford1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as abright yellow solid (272 mg, 96% yield).

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline: To apressure vessel was added1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide (272 mg,0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The vessel wasconnected to a Parr apparatus, evacuated, and refilled with nitrogen.The vessel was then evacuated and filled with hydrogen gas to a pressureof 50 psi. The reaction mixture was shaken under 50 psi for 4 h. Themixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a graysolid (211 mg, 87% yield).

Example 485-chloro-N⁴-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N²-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine

The compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with5-(propan-2-yl)-1,3-oxazol-2-amine.

Example 495-chloro-N²-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N⁴-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine

The compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine(as described in Example 47) with 1-(4-fluorobenzyl)-1H-pyrrol-3-amine.

Example 502-{[(5-chloro-4-{[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]amino}pyrimidin-2-yl)amino]methyl}-N,N-diethylthiophene-3-sulfonamide

The compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine(as described in Example 47) with2-(aminomethyl)-N,N-diethylthiophene-3-sulfonamide.

Example 51N²-[5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N⁴-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared In example 33)with 2,4,5-trichloropyrimidine to generate2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine.2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amineis then reacted with 5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-amineaccording to the procedure described in Example 321.

Example 525-chloro-N⁴-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N²-{[5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine(as described in Example 51) with1-[5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methanamine.

Example 535-chloro-N⁴-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N²-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with2,4,5-trichloropyrimidine to generate2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine.2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amineis then reacted with5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-amine according tothe procedure described in Example 32.

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline

4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene: At 0 degree, to astirring solution of 4-Bromo-2-Floronitroaniline (2.0 g, 9.1 mmol) inDCM was added Sodium Isopropoxide (2.0 g, 20 mmol) in two portions. Thereaction mixture was warmed to room temperature and stirred overnight.The reaction mixture was filtered through a syringe filter. The productwas isolated by prep-HPLC (water/Acetonitrile) as a bright yellow solid(0.8 g, 2.9 mmol, 32% yield).

4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene: To a stirring solutionof 4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene (0.8 g, 2.9 mmol) inAcetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous solution,0.6 mL, 5.8 mmol). The reaction mixture was heated to 110 degrees C. for2 hours in oil bath. The reaction mixture was treated with saturatedSodium Sulfide aqueous solution and basified with saturated sodiumbicarbonate solution. The mixture was extracted with Ethyl Acetate andthe combined organic layers were dried over sodium sulfate. The organicsolvent was removed under reduced pressure and the residue was used forthe next step reaction without further purification.

Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide: To astirring solution of 4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene(0.44 g, 1.6 mmol) and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1mL of DMF, was added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc)₂(18 mg, 0.08 mmol), Xanphos (55 mg, 0.10 mmol). The reaction mixture wasstirred at 110 degrees C. overnight. The reaction mixture was cooled toroom temperature and filtered through celite. The desired product wasisolated through prep-HPLC to yield a brownish yellow solid (0.24 g, 55%yield)

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: To a solution ofdimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g,0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24 mg) andstirred under hydrogen overnight. The reaction mixture was filtered andthe organic solvent was removed under reduced pressure. The residue waspurified by prep-HPLC to yield 100 mg of desired product (50% yield).

Example 545-chloro-N⁴-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N²-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(as described in Example 53) with1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.

Example 55N²-benzyl-5-chloro-N⁴-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(as described in Example 53) with benzylamine.

Example 565-chloro-N²-(5-cyclopropyl-1,3-oxazol-2-yl)-N⁴-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]anilinewith 2,4,5-trichloropyrimidine to generate2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine.2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amineis then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to theprocedure described in Example 32.

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline

tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate: Asolution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) washeated at reflux for 16 h. The reaction mixture was concentrated invacuo and the residue was purified by silica gel chromatography (0-10%7N ammonia in methanol:dichloromethane) to afford the desired compoundas a white solid (178 mg, 38% yield).

1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide: To a stirring solution of tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178mg, 0.563 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (0.5mL). After 20 min, the solution was concentrated and the resultingresidue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16mmol) was added portionwise to the stirring solution followed by5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture washeated to 50° C. After 2 h, the reaction mixture was concentrated andthe residue was purified by silica gel chromatography (0-10% 7N ammoniain methanol:dichloromethane) to afford the compound as a bright yellowsolid (176 mg, 86% yield).

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline:To a pressure vessel was added1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). Thevessel was connected to a Parr apparatus, evacuated, and refilled withnitrogen. The vessel was then evacuated and filled with hydrogen gas toa pressure of 50 psi. The reaction mixture was shaken under 50 psi for 4h. The mixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded the compound as a graysolid (178 mg, 98% yield).

Example 575-chloro-N²-(5-cyclopropyl-1,3-oxazol-2-yl)-N⁴-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline with2,4,5-trichloropyrimidine to generate2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidin-4-amine.2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidin-4-amineis then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to theprocedure described in Example 32.

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline

Diethyl (3-methoxy-4-nitrophenyl)phosphonate: To a solution of5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was addeddiethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27mmol), XantPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g,5.86 mmol). The mixture was purged with nitrogen, and subjected tomicrowaves at 150° C. for 20 minutes. The reaction mixture wasconcentrated and purified by silica gel chromatography (0-45% ethylacetate:heptane) to afford the desired product (0.504 g, 33% yield).

(3-methoxy-4-nitrophenyl)phosphonic dichloride: To a solution of diethyl(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL DMFwas added thionyl chloride (5.7 mL, 78.5 mmol). The reaction flask wasequipped with a reflux condenser and the mixture was heated to reflux.After 2 h at reflux, the reaction was cooled to rt and concentrated invacuo. The crude oil was redissolved in CH₂Cl₂ and heptane was added toprecipitate the desired compound. The clear solution was decanted andthe precipitate was collected and dried dried to afford the desiredcompound as a white solid (1.39 g, 33% yield).

Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide: To a solution of(3-methoxy-4-nitrophenyl)phosphonic dichloride (1.39 g, 5.15 mmol) in 15mL THF at −78° C. under nitrogen was slowly added vinylmagnesium bromide(10.3 mL, 1.0 M in THF). After the addition was complete, the reactionstirred at −78° C. for an additional hour. The cold reaction mixture wasquenched by the addition of saturated NH₄Cl (20 mL) and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed with 1 MNaOH, brine, and dried over MgSO₄. The organic extracts were filteredand concentrated to provide Diethenyl(3-methoxy-4-nitrophenyl)phosphaneoxide (0.982 g, 75%).

1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide:Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol),ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) weredissolved in 50% aqueous THF (5 mL) and heated to 105° C. undernitrogen. After one hour, another portion of benzylamine was added tothe reaction mixture. The reaction mixture was refluxed for anadditional 2 h, and then cooled to rt. The reaction mixture waspartitioned between saturated aqueous NaHCO₃ and CH₂Cl₂. The aqueousphase was washed once with CH₂Cl₂ and the organic layers were combined.The organic extracts were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the compound(0.267 g, 46% yield).

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline: To asolution of 1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane4-oxide (0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with aseptum, evacuated, and refilled with hydrogen. The flask was equippedwith a hydrogen balloon and the reaction stirred for 3 h. The flask wasthen evacuated and refilled with nitrogen. The reaction mixture wasfiltered through Celite and concentrated to provide the crude compoundas the hydrochloride salt, which was used without purification.

Example 585-chloro-N²-(2-cyclopropyl-1,3-oxazol-5-yl)-N⁴-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidine-2,4-diamine

This compound can be prepared as in Example 32 by reacting4-(diethylphosphoryl)-2-methoxyaniline with 2,4,5-trichloropyrimidine to2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine.2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amineis then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to theprocedure described in Example 32.

4-(Dipropylphosphoryl)-2-methoxyaniline

To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mLDMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladiumacetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), andpotassium phosphate (0.116 g, 0.544 mmol). The mixture was purged withnitrogen, and subjected to microwaves at 150° C. for 20 minutes. Thereaction mixture was concentrated and purified by silica gelchromatography (0-12% 7N ammonia in methanol:dichloromethane) and thefractions were concentrated. The residue was acidified with 2.5 M HCl inethanol and the solution was concentrated to provide4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132g, 91% yield).

Example 59N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine

6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine: A suspensionof 4-amino-dimethylphenylphosphine oxide (2.2 mmol) in 15 mL ofN,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine, is stirred atroom temperature until a clear solution is obtained.4,6-Dichloropyrimidine (2.6 mmol) is added in four portions over 5minutes. The reaction mixture is stirred at high temperature untilformation of the desired compound.

N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine:To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072 mmol)in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Methylpiperazine (0.072 mmol). The mixture can be microwaved at 120 degrees.The reaction mixture can then be filtered through a syringe filter andcan be purified by prep-HPLC.

Example 60N-[4-(dimethylphosphoryl)phenyl]-N′-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrimidine-4,6-diamine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.078 mmol) in 1.5 mL of ethanol is added 10 μL oftriethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture canbe microwaved at 120 degrees until formation of the desired compound.The reaction mixture can then be filtered through a syringe filter andpurified by prep-HPLC.

Example 61N-[4-(dimethylphosphoryl)phenyl]-N′-(morpholin-4-ylmethyl)pyrimidine-4,6-diamine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and 4-(2-aminoethyl) morpholine (15 mg, 0.12 mmol). Themixture can be microwaved at 120 degrees until formation of the desiredcompound. The reaction mixture can be filtered through a syringe filterand purified by prep-HPLC.

Example 624-{2-[(6-{[4-(dimethylphosphoryl)phenyl]amino}pyrimidin-4-yl)amino]ethyl}benzenesulfonamide

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12mmol). The mixture can be microwaved at 120 degrees until formation ofthe desired compound. The reaction mixture can be filtered through asyringe filter and purified by prep-HPLC.

Example 63N-[4-(dimethylphosphoryl)phenyl]-N′-(tetrahydrofuran-2-yl)pyrimidine-4,6-diamine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt (14 mg,0.12 mmol). The mixture is microwaved at 120 degrees until formation ofthe desired compound. The reaction mixture can then be filtered througha syringe filter and purified by prep-HPLC.

Example 64N-[4-(dimethylphosphoryl)phenyl]-N′-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4,6-diamine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and 3-Amino-3-azabicyclo-[3,3,0] octane hydrochloride salt(19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees untilformation of the desired compound. The reaction mixture can then befiltered through a syringe filter and purified by prep-HPLC.

Example 65N-[4-(dimethylphosphoryl)phenyl]-N′-(morpholin-4-yl)pyrimidine-4,6-diamine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture ismicrowaved at 120 degrees until formation of the desired compound. Thereaction mixture can then be filtered through a syringe filter andpurified by prep-HPLC.

Example 66N-[4-(dimethylphosphoryl)phenyl]-6-(4-phenylpiperazin-1-yl)pyrimidin-4-amine

To a solution of6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared asin Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL oftriethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture ismicrowaved at 120 degrees until formation of the desired compound. Thereaction mixture can then be filtered through a syringe filter andpurified by prep-HPLC.

Example 67N-[4-(dimethylphosphoryl)phenyl]-N′-[2-(1H-indol-3-yl)ethyl]pyrimidine-4,6-diamine

The compound is prepared as in Example 59 by reacting6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine withTryptamine.

Example 68

N-[4-(dimethylphosphoryl)phenyl]-N′-(4-methylpiperazin-1-yl)pyrimidine-4,6-diamine

The compound is prepared as in Example 59 by reacting6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with1-Amino-4-methyl-piperazine.

Example 69N-[4-(dimethylphosphoryl)phenyl]-N′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrimidine-4,6-diamine

The compound is prepared as in Example 59 by reacting6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with1-adamantanemethylamine.

Example 70N-[4-(dimethylphosphoryl)phenyl]-N′-[4-(4-methylpiperazin-1-yl)benzyl]pyrimidine-4,6-diamine

The compound is prepared as in Example 59 by reacting6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with4-(4-methylpiperazine)-benzylamine.

Example 71N-(3,5-dimethylphenyl)-N′-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-diamine

The compound is prepared as in Example 59 by reacting6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with3,5-dimethylaniline.

Example 72

N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N′-phenylpyrimidine-4,6-diamine

6-chloro-2-methyl-N-phenylpyrimidin-4-amine: To a solution of Aniline(205 mg, 2.2 mmol) and 4,6-dichloro-2-methylpyrimidine (2.7 mmol) in 5mL of Ethanol, is added 500 mg of Potassium carbonate. The reactionmixture is stirred at room temperature until formation of the desiredcompound. Solvent is removed under reduced pressure. The residue can bepurified by silica gel flash chromatography.

(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide: To a solution of5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was addeddimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg,0.13 mmol), XANPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C.for 18 h. The reaction mixture was basified with saturated sodiumbicarbonate solution, and extracted with ethyl acetate. The organiclayer was concentrated and purified by prep-HPLC to give the finalproduct (0.16 g, 30% yield). MS/ES+: m/z=229.

4-(dimethylphosphoryl)-2-methoxyaniline: To a solution of(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) in5 mL of EtOH was added 10% weight of palladium on carbon (0.2 g). Themixture was purged with argon, and hydrogenated under 30 psi for 2 h.The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.088 g,86% yield). MS/ES+: m/z=199.

N-[4-(dimethylphosphoryl))-2-methoxyphenyl]-2-methyl-N′-phenylpyrimidine-4,6-diamine:To a solution of 6-chloro-2-methyl-N-phenylpyrimidin-4-amine (0.35 mmol)and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mLof DMF, is added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixturecan be heated in a sealed tube at 140 degrees until formation of thedesired compound. The reaction mixture is filtered through a syringefilter and can be purified by Prep-HPLC.

Example 73N³-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine: To asolution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in4 mL of N,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100mg) and the reaction mixture is allowed to stirred at 0 degree for 20minutes. 3,5-dichloropyridazine (1.6 mmol) is added and the reactionmixture is warmed to room temperature. The reaction mixture is stirredat room temperature until formation of the desired compound. Thereaction mixture is quenched with water and extracted with Ethylacetate. The combined Ethyl acetate layers are dried over Sodium Sulfateand solvent is removed under reduced pressure. The residue can bepurified by Prep-HPLC.

N³-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (0.02 mmol)and 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example72:15 mg, 0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5MHCl in Ethanol. The reaction mixture is heated in a sealed tube at 140degree until formation of the desired compound. The reaction mixture isfiltered through a syringe filter and can be purified by Prep-HPLC.

Example 74N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazin-3-amine

3-chloro-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazine: To asolution of 3-fluoro-5-(trifluoromethyl)phenol (1.6 mmol) in 4 mL ofN,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100 mg) andthe reaction mixture is allowed to stirred at 0 degree for 20 minutes.3,5-dichloropyridazine (1.6 mmol) is added and the reaction mixture iswarmed to room temperature. The reaction mixture is stirred at roomtemperature until formation of the desired compound. The reactionmixture is quenched with water and extracted with Ethyl acetate. Thecombined Ethyl acetate layers are dried over Sodium Sulfate and solventis removed under reduced pressure. The residue can be purified byPrep-HPLC.

N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazin-3-amine:To a solution of3-chloro-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazine (0.02 mmol)and 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example72:15 mg, 0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5MHCl in Ethanol. The reaction mixture is heated in a sealed tube at 140degree until formation of the desired compound. The reaction mixture isfiltered through a syringe filter and can be purified by Prep-HPLC.

Example 75N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine

6-chloro-N-[4-(dimethylphosphoryl)phenyl]-2-methylpyrimidin-4-amine: Toa solution of 4,6-dichloro-2-methylpyrimidine (1.31 mmol) in 1 mL of DMFis added 4-(dimethylphosphoryl) aniline (0.221 g, 1.31 mmol) andpotassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at 110°C. until formation of the desired compound. The reaction mixture isbasified with saturated sodium bicarbonate solution. The suspension isfiltered and washed with ethyl acetate.

1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine: To asolution of 5-fluoro-2-nitroanisoole (0.5 g, 2.92 mmol) in 3 mL of DMFwas added 1-methyl-4-(piperidin)piperazine (0.536 g, 2.92 mmol) andpotassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120°C. for 18 h. The mixture was basified with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer waspurified by chromatography to give final product as yellow solid (0.95g, 95% yield). MS/ES+: m/z=334.

2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline: The asolution of1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g,0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladiumon carbon (0.060 g). The hydrogenation was finished under 30 psi after 4h. The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.15 g,88% yield). MS/ES+: m/z=334.

N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine:Tothe compound6-chloro-2-methyl-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(0.16 mmol) in 1 mL of 2-methoxyethanol is added2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g,0.16 mmol). The mixture is stirred at 110° C. until formation of thedesired compound. The mixture is basified with saturated sodiumbicarbonate solution and extracted with limited amount of ethyl acetate.The compound can be purified by chromatography.

Example 76N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine

6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine: To a solution of6-bromo-2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (77.2 mg, 39% yield).

6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine: To asolution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol)in 2 mL of DMF at 0° C. is added NaH (60% in oil, 0.349 g, 8.72 mmol) inone portion. After stirring for 20min, 4,6-dichloropyrimidine can beadded. The mixture is stirred at 0° C. for 30 minutes, and then at roomtemperature until formation of the desired compound. After quenchingwith saturated ammonium chloride solution, the mixture is poured inwater and ethyl acetate mixture. The compound can be purified by HPLC.

N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine: To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl] pyrimidin-4-amine (0.250mmol) in 1 mL of 2-methoxyethanol is added6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol)and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in a sealedtube at 90° C. until formation of the desired compound. The mixture isbasified with 1N NaOH solution, and extracted with ethyl acetate. Theorganic layers can be combined, washed with saturated sodium chloridesolution, dried with sodium sulfate, filtered and concentrated. Thecrude residue can be purified by silica gel chromatography.

Example 77N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine

5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine: To a solution of5-bromo-3-methoxypyrazin-3-ylamine (0.204 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (126 mg, 63% yield).

5-chloro-N²-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a mixture of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared inExample 76:0.348 mmol) and5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348 mmol) isadded tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17.6mg, 0.017 mmol), XANTPHOS (23.3 mg, 0.040 mmol), and cesium carbonate(0.228 g, 0.700 mmol), and dioxane (3.5 mL). The tube is sealed andheated at 120° C. until formation of the desired compound. The reactionmixture is then cooled to room temperature and concentrated. The cruderesidue can be purified by silica gel chromatography.

Example 77N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N′-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared inExample 76:0.054 mmol) in 0.5 mL of 2-methoxyethanol in a vial is added4-(dimethylphosphoryl)-2-methyoxyaniline (prepared in Example 73: 0.044mmol) as the HCl salt. The vial is sealed and the reaction is heated at90° C. until formation of the desired compound. The reaction is quenchedwith 1N NaOH solution and the solution extracted ethyl acetate. Theorganic layers are combined, washed with saturated sodium chloridesolution, dried with sodium sulfate, filtered and concentrated. Thecrude residue can be purified by silica gel chromatography.

Example 79N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyridine-2,4-diamine

2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine: To a solutionof 2-chloro-4-iodo-5-methylpyridine (2.00 mmol) in 8 mL toluene is added1-amino-2-(isopropylsulphonyl)benzene (2.20 mmol), palladium acetate(22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and cesiumcarbonate (2.20 mmol). The mixture is purged with nitrogen, and can besubjected to microwaves at 100° C. until formation of2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine. Thereaction mixture can then be concentrated and purified by silica gelchromatography.

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyridine-2,4-diamine: To a solution of2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine (0.12 mmol) in1 mL of 2-methoxyethanol is added4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 72: 0.12mmol) and 49 μL of 2.5 M HCl in ethanol. The mixture is heated in asealed tube at 90° C. until formation of the desired compound. Themixture is then basified with 1N NaOH solution, and extracted with ethylacetate. The organic layers can be combined, washed with saturatedsodium chloride solution, dried with sodium sulfate, filtered andconcentrated. The crude residue can be purified by prep-HPLC to affordthe final compound.

Example 80N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine:To a solution of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (2.00 mmol)in 8 mL toluene is added 1-amino-2-(isopropylsulphonyl)benzene (2.20mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,0.120 mmol), and cesium carbonate (2.20 mmol). The mixture is purgedwith nitrogen, and can be subjected to microwaves at 100° C. untilformation of2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine. Thereaction mixture can then be concentrated and purified by silica gelchromatography.

N²-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N⁴-[2-(propan-2-ylsulfonyl)phenyl]pyridine-2,4-diamine:To a solution of2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine(0.12 mmol) in 1 mL of 2-methoxyethanol is added4-(dimethylphosphoryl)-2-methoxyaniline(prepared as in Example 72: 0.12mmol) and 49 μL of 2.5 M HCl in ethanol. The mixture is heated in asealed tube at 90° C. until formation of the desired compound. Themixture is then basified with 1N NaOH solution, and extracted with ethylacetate. The organic layers can be combined, washed with saturatedsodium chloride solution, dried with sodium sulfate, filtered andconcentrated. The crude residue can be purified by prep-HPLC to affordthe final compound.

Example 81N²-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 5-(Dimethylphosphoryl)-2-methoxyaniline.

5-(Dimethylphosphoryl)-2-methoxy aniline: To a solution of5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.365 g, 85% yield).

Example 82N²-[4-(dimethylphosphoryl)-2-methylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 4-(Dimethylphosphoryl)-2-methylaniline.

4-(Dimethylphosphoryl)-2-methylaniline: To a solution of4-bromo-2-methylaniline (0.372 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.313 g, 85% yield).

Example 83N²-[4-(dimethylphosphoryl)-2-ethylphenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 4-(Dimethylphosphoryl)-2-ethylaniline.

4-(Dimethylphosphoryl)-2-ethylaniline: To a solution of4-bromo-2-ethylaniline (0.400 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.308 g, 78% yield).

Example 84N²-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline.

4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline: To a solution of4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF wasadded dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate(22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl inmethanol to afford the desired product as its hydrochloride salt (0.573g, 98% yield).

Example 85N²-[2-chloro-4-(dimethylphosphoryl)phenyl]-N⁴-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 2-chloro-4-(dimethylphosphoryl)-aniline.

2-Chloro-4-(dimethylphosphoryl)aniline: To a solution of2-chloro-4-iodoaniline (0.507 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.340 g, 83% yield).

Example 86N²-[4-(dimethylphosphoryl)-2-fluorophenyl]-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

This compound can be prepared as described in Example 80 by reacting2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-aminewith 4-(dimethylphosphoryl)-2-fluoroaniline.

4-(Dimethylphosphoryl)-2-fluoroaniline: To a solution of4-bromo-2-fluoroaniline (0.380 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (73.5 mg, 20% yield).

Example 87N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N′-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline

4-bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene: At 0 degree, to astirring solution of 4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) inDCM was added Sodium 2-propane thiolate (2.0 g, 20 mmol) in twoportions. The reaction mixture was warmed to room temperature andstirred overnight. The reaction mixture was filtered through a syringefilter. The product was isolated by prep-HPLC (water/Acetonitrile) as abright yellow solid (0.8 g, 2.9 mmol, 32% yield).

4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene: To a stirring solutionof 4-bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene (0.8 g, 2.9 mmol) inAcetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous solution,0.6 mL, 5.8 mmol). The reaction mixture was heated to 110 degrees C. for2 hours in oil bath. The reaction mixture was treated with saturatedSodium Sulfide aqueous solution and basified with saturated sodiumbicarbonate solution. The mixture was extracted with Ethyl Acetate andthe combined organic layers were dried over sodium sulfate. The organicsolvent was removed under reduced pressure and the residue was used forthe next step reaction without further purification.

Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide: To astirring solution of 4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene(0.44 g, 1.6 mmol) and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1mL of DMF, was added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc)₂(18 mg, 0.08 mmol), Xanphos (55 mg, 0.10 mmol). The reaction mixture wasstirred at 110 degrees C. overnight. The reaction mixture was cooled toroom temperature and filtered through celite. The desired product wasisolated through prep-HPLC to yield a brownish yellow solid (0.24 g, 55%yield)

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: To a solution ofdimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g,0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24 mg) andstirred under hydrogen overnight. The reaction mixture was filtered andthe organic solvent was removed under reduced pressure. The residue waspurified by prep-HPLC to yield 100 mg of desired product (50% yield).

6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine:To a solution of 4,6-dichloropyrimidine (1.31 mmol) in 1 mL of DMF isadded 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: (1.31 mmol)and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at110° C. until formation of the desired compound. The reaction mixture isbasified with saturated sodium bicarbonate solution. The suspension isfiltered and washed with ethyl acetate.

N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N′-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine:To the compound6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine(0.16 mmol) in 1 mL of 2-methoxyethanol is added2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (preparedin Example 75: 0.71 g, 0.16 mmol). The mixture is stirred at 110° C.until formation of the desired compound. The mixture is basified withsaturated sodium bicarbonate solution and extracted with limited amountof ethyl acetate. The compound can be purified by chromatography.

Example 88N³-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline

Diethyl (3-methoxy-4-nitrophenyl)phosphonate: To a solution of5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was addeddiethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27mmol), XANTPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g,5.86 mmol). The mixture was purged with nitrogen, and subjected tomicrowaves at 150° C. for 20 minutes. The reaction mixture wasconcentrated and purified by silica gel chromatography (0-45% ethylacetate:heptane) to afford the desired product (0.504 g, 33% yield).

(3-methoxy-4-nitrophenyl)phosphonic dichloride: To a solution of diethyl(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL DMFwas added thionyl chloride (5.7 mL, 78.5 mmol). The reaction flask wasequipped with a reflux condenser and the mixture was heated to reflux.After 2 h at reflux, the reaction was cooled to rt and concentrated invacuo. The crude oil was redissolved in CH₂Cl₂ and heptane was added toprecipitate the desired compound. The clear solution was decanted andthe precipitate was collected and dried dried to afford the desiredcompound as a white solid (1.39 g, 33% yield).

Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide: To a solution of(3-methoxy-4-nitrophenyl)phosphonic dichloride (1.39 g, 5.15 mmol) in 15mL THF at −78° C. under nitrogen was slowly added vinylmagnesium bromide(10.3 mL, 1.0 M in THF). After the addition was complete, the reactionstirred at −78° C. for an additional hour. The cold reaction mixture wasquenched by the addition of saturated NH₄Cl (20 mL) and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed with 1 MNaOH, brine, and dried over MgSO₄. The organic extracts were filteredand concentrated to provide Diethenyl(3-methoxy-4-nitrophenyl)phosphaneoxide (0.982 g, 75%).

1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide:Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol),ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) weredissolved in 50% aqueous THF (5 mL) and heated to 105° C. undernitrogen. After one hour, another portion of benzylamine was added tothe reaction mixture. The reaction mixture was refluxed for anadditional 2 h, and then cooled to rt. The reaction mixture waspartitioned between saturated aqueous NaHCO₃ and CH₂Cl₂. The aqueousphase was washed once with CH₂Cl₂ and the organic layers were combined.The organic extracts were washed with brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the compound(0.267 g, 46% yield).

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline: To asolution of 1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane4-oxide (0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with aseptum, evacuated, and refilled with hydrogen. The flask was equippedwith a hydrogen balloon and the reaction stirred for 3 h. The flask wasthen evacuated and refilled with nitrogen. The reaction mixture wasfiltered through Celite and concentrated to provide the crude compoundas the hydrochloride salt, which was used without purification.

N³-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared inExample 73:0.02 mmol) and4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol)in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. Thereaction mixture is heated in a sealed tube at 140 degree untilformation of the desired compound. The reaction mixture is filteredthrough a syringe filter and can be purified by Prep-HPLC.

Example 89N³-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline

1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide: To a solution ofmethylphosphonic dischloride (10.0 g, 75.2 mmol) in CH₂Cl₂ at −78° C.,was added vinylmagnesium bromide (175 mL, 1.0 M in THF) via additionfunnel over 4 h. The solution was warmed to 0° C. and quenched with aminimum amount of saturated NH₄Cl. The mixture was filtered through apad of silica gel and silica was extracted with 10% 7N ammonia inmethanol:dichloromethane. The solution was concentrated under reducedpressure to afford methyl divinyl phosphine oxide as a viscous, yellowoil that was used without purification.

A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) andbenzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated atreflux for 16 h. The reaction mixture was concentrated in vacuo and theresidue was purified by silica gel chromatography (0-10% 7N ammonia inmethanol: dichloromethane) to afford1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g,70% yield).

4-methyl-[1,4]azaphosphinane-4-oxide: A flask was charged with1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol) and10% Pd/C (100 mg). The flask was evacuated and filled with nitrogen.Anhydrous methanol (18 mL) was added to the flask and the flask wasequipped with a reflux condenser with a nitrogen inlet. Ammonium formate(2.25 g, 35.8 mmol) was added in one portion at room temperature. Theresulting mixture was stirred at reflux for 2 h. The reaction wasfiltered through a Celite pad and the Celite was washed with 2×5 mLmethanol. The combined filtrate and washing was evaporated in vacuo. Thecrude residue was purified by silica gel chromatography (0-10% 7Nammonia in methanol:dichloromethane) to afford4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%yield).

1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide: Amixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol),5-fluoro-2-nitroanisole (340 mg, 2.00 mmol), K₂CO₃ (345 mg, 2.50 mmol),and DMF (5 mL) was heated to 50° C. After 2 h, the reaction mixture wasconcentrated and purified by silica gel chromatography (0-5% 7N ammoniain methanol:dichloromethane) to afford1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as abright yellow solid (272 mg, 96% yield).

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline: To apressure vessel was added1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide (272 mg,0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The vessel wasconnected to a Parr apparatus, evacuated, and refilled with nitrogen.The vessel was then evacuated and filled with hydrogen gas to a pressureof 50 psi. The reaction mixture was shaken under 50 psi for 4 h. Themixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a graysolid (211 mg, 87% yield).

N³-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared inExample 73:0.02 mmol) and2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol)in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. Thereaction mixture is heated in a sealed tube at 140 degree untilformation of the desired compound. The reaction mixture is filteredthrough a syringe filter and can be purified by Prep-HPLC.

Example 90N³-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline

tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate: Asolution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) washeated at reflux for 16 h. The reaction mixture was concentrated invacuo and the residue was purified by silica gel chromatography (0-10%7N ammonia in methanol:dichloromethane) to afford the desired compoundas a white solid (178 mg, 38% yield).

1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide: To a stirring solution of tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178mg, 0.563 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (0.5mL). After 20 min, the solution was concentrated and the resultingresidue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16mmol) was added portionwise to the stirring solution followed by5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture washeated to 50° C. After 2 h, the reaction mixture was concentrated andthe residue was purified by silica gel chromatography (0-10% 7N ammoniain methanol:dichloromethane) to afford the compound as a bright yellowsolid (176 mg, 86% yield).

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline:To a pressure vessel was added1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). Thevessel was connected to a Parr apparatus, evacuated, and refilled withnitrogen. The vessel was then evacuated and filled with hydrogen gas toa pressure of 50 psi. The reaction mixture was shaken under 50 psi for 4h. The mixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded the compound as a graysolid (178 mg, 98% yield).

N³-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared inExample 73:0.02 mmol) and2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline(0.7mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl inEthanol. The reaction mixture is heated in a sealed tube at 140 degreeuntil formation of the desired compound. The reaction mixture isfiltered through a syringe filter and can be purified by Prep-HPLC.

Example 91N³-[4-(diethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

4-(Dipropylphosphoryl)-2-methoxyaniline

To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mLDMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladiumacetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), andpotassium phosphate (0.116 g, 0.544 mmol). The mixture was purged withnitrogen, and subjected to microwaves at 150° C. for 20 minutes. Thereaction mixture was concentrated and purified by silica gelchromatography (0-12% 7N ammonia in methanol:dichloromethane) and thefractions were concentrated. The residue was acidified with 2.5 M HCl inethanol and the solution was concentrated to provide4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132g, 91% yield).

N³-[4-(diethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine:To a solution of6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared inExample 73:0.02 mmol) and 4-(Dipropylphosphoryl)-2-methoxyaniline (0.7mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl inEthanol. The reaction mixture is heated in a sealed tube at 140 degreeuntil formation of the desired compound. The reaction mixture isfiltered through a syringe filter and can be purified by Prep-HPLC.

Example 92N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine

4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine: Asuspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, canbe stirred at room temperature for 15 minutes until a clear solution isobtained. 2,4-Dichloro-1,3,5-triazine (2.6 mmol) is added in fourportions over 5 minutes. The reaction mixture is stirred at 60 degreesfor 1 hour. The reaction mixture is cooled to room temperature, filteredand purified by prep-HPLC.

N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine:To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Methylpiperazine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120degrees until formation of the desired compound. The reaction mixture isfiltered through a syringe filter and purified by prep-HPLC.

Example 93N-[4-(dimethylphosphoryl)phenyl]-N′-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.078 mmol) in 1.5 mL of ethanol is added 10μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). Themixture can be microwaved at 120 degrees until formation of the desiredcompound. The reaction mixture is filtered through a syringe filter andpurified by prep-HPLC.

Example 94N-[4-(dimethylphosphoryl)phenyl]-N′-(morpholin-4-ylmethyl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 4-(2-aminoethyl) morpholine (15 mg, 0.12 mmol). Themixture can be microwaved at 120 degrees until formation of the desiredcompound. The reaction mixture is filtered through a syringe filter andpurified by prep-HPLC.

Example 954-{2-[(4-{[4-(dimethylphosphoryl)phenyl]amino}-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12mmol). The mixture can be microwaved at 120 degrees until formation ofthe desired compound. The reaction mixture is filtered through a syringefilter and purified by prep-HPLC.

Example 96N-[4-(dimethylphosphoryl)phenyl]-N′-(tetrahydrofuran-2-yl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt (14mg, 0.12 mmol). The mixture can be microwaved at 120 degrees untilformation of the desired compound. The reaction mixture is filteredthrough a syringe filter and purified by prep-HPLC.

Example 97N-[4-(dimethylphosphoryl)phenyl]-N′-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 3-Amino-3-azabicyclo-[3,3,0] octane hydrochloridesalt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees untilformation of the desired compound. The reaction mixture is filteredthrough a syringe filter and purified by prep-HPLC.

Example 98N-[4-(dimethylphosphoryl)phenyl]-N′-(morpholin-4-yl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixtureis microwave at 120 degrees until formation of the desired compound. Thereaction mixture is filtered through a syringe filter and purified byprep-HPLC.

Example 99N-[4-(dimethylphosphoryl)phenyl]-4-(4-phenylpiperazin-1-yl)-1,3,5-triazin-2-amine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixtureis microwaved at 120 degrees until formation of the desired compound.The reaction mixture is filtered through a syringe filter and purifiedby prep-HPLC.

Example 100N-[4-(dimethylphosphoryl)phenyl]-N′-[2-(1H-indol-3-yl)ethyl]-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture ismicrowaved at 120 degrees until formation of the desired compound. Thereaction mixture is filtered through a syringe filter and purified byprep-HPLC.

Example 101N-[4-(dimethylphosphoryl)phenyl]-N′-(4-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine

To a solution of4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μLof triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). Themixture is microwaved at 120 degrees until formation of the desiredcompound. The reaction mixture is filtered through a syringe filter andpurified by prep-HPLC.

Example 1026-chloro-N-[4-(dimethylphosphoryl)phenyl]-N′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1,3,5-triazine-2,4-diamine

4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine: Asuspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine iscooled to 0° C. 2,4,6-trichloro-1,3,5-triazine (2.6 mmol) is added infour portions over 5 minutes. The reaction mixture is warmed up to roomtemperature and stirred until formation of the desired compound. Thereaction mixture is filtered and purified by prep-HPLC.

6-chloro-N-[4-(dimethylphosphoryl)phenyl]-N′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1,3,5-triazine-2,4-diamine:To a solution of4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(0.072 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and1-(1-adamantyl)-methanamine (7.2 mg, 0.072 mmol). The mixture can bemicrowaved at 120 degrees for 20 minutes. The reaction mixture isfiltered through a syringe filter and purified by prep-HPLC.

Example 1036-chloro-N-[4-(dimethylphosphoryl)phenyl]-N′-[4-(4-methylpiperazin-1-yl)benzyl]-1,3,5-triazine-2,4-diamine

To a solution of4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50μL of triethylamine and 4-(4-methylpiperazine)-benzylamine (24 mg, 0.12mmol). The mixture is microwaved at 120 degrees until formation of thedesired compound. The reaction mixture is filtered through a syringefilter and purified by prep-HPLC.

Example 1046-chloro-N-(3,5-dimethylphenyl)-N′-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazine-2,4-diamine

To a solution of4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine(prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50μL of triethylamine and 3,5-dimethylaniline (24 mg, 0.12 mmol). Themixture is microwaved at 120 degrees until formation of the desiredcompound. The reaction mixture is filtered through a syringe filter andpurified by prep-HPLC.

Example 1056-chloro-N³-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-phenyl-1,2,4-triazine-3,5-diamine

3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine: To a solution of Aniline(205 mg, 2.2 mmol) and 3,5,6-trichloro-1,2,4-triazine (2.7 mmol) inCH₂Cl₂, is added triethylamine (3 mmol). The reaction mixture is stirredat room temperature until formation of the desired product. Solvent isremoved under reduced pressure. The residue can be purified by silicagel flash chromatography.

(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide: To a solution of5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was addeddimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg,0.13 mmol), XANTPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C.for 18 h. The reaction mixture was basified with saturated sodiumbicarbonate solution, and extracted with ethyl acetate. The organiclayer was concentrated and purified by prep-HPLC to give the finalproduct (0.16 g, 30% yield). MS/ES+: m/z=229.

4-(dimethylphosphoryl)-2-methoxyaniline: To a solution of(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) in5 mL of EtOH was added 10% weight of palladium on carbon (0.2 g). Themixture was purged with argon, and hydrogenated under 30 psi for 2 h.The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.088 g,86% yield). MS/ES+: m/z=199.

6-chloro-N⁴-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-phenyl-1,2,4-triazine-3,5-diamine:A mixture of 3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine (1 mmol),4-(dimethylphosphoryl)-2-methoxyaniline (1 mmol) and camphorsulfonicacid (0.7equiv.), is refluxed for 20-48 h in 2-propanol. The reactionmixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 1066-chloro-N³-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine: Toa solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol)and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH₂Cl₂, is addedtriethylamine (2 mmol). The reaction mixture is allowed to cool to roomtemperature, dissolved in dichloromethane and washed with an aqueoussolution of Na₂CO₃. The dichloromethane extract is dried over MgSO₄ andevaporated. The crude product is purified by Prep-HPLC.

6-chloro-N³-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (1mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example105: 1 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for20-48 hours in 2-propanol. The reaction mixture is allowed to cool toroom temperature, dissolved in dichloromethane and washed with anaqueous solution of Na₂CO₃. The dichloromethane extract is dried overMgSO₄ and evaporated. The crude product is purified by Prep-HPLC.

Example 1076-chloro-N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-{[3-fluoro-5-(trilluoromethyl)phenyl]sulfanyl}-1,2,4-triazin-3-amine

3,6-dichloro-5-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfanyl}-1,2,4-triazine:To a solution of 3,5,6-trichloro-1,2,4-triazine (3 mmol) in dry THF(30mL) at −78° C. under nitrogen atmosphere is added3-fluoro-5-(trifluoromethyl)benzenethiol (3 mmol) and sodium carbonate(3 mmol). The reaction is allowed to reach room temperature and isstirred at room temperature until formation of the desired compound. Thesolvent is evaporated. The residue is suspended in water and extractedwith CH₂Cl₂. The dichloromethane solution is dried over MgSO₄ andevaporated. The residue is chromatographed on a silica gel column.

6-chloro-N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfanyl}-1,2,4-triazin-3-amine:A mixture of3,6-dichloro-5-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfanyl}-1,2,4-triazine(0.7 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as inExample 105: 15 mg, 0.7 mmol) and camphorsulfonic acid (0.7 equiv.), isrefluxed for 20-48 hours in 2-propanol. The reaction mixture is allowedto cool to room temperature, dissolved in dichloromethane and washedwith an aqueous solution of Na₂CO₃. The dichloromethane extract is driedover MgSO₄ and evaporated. The crude product is purified by Prep-HPLC.

Example 1086-chloro-N⁵-[4-(dimethylphosphoryl)phenyl]-N³-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine

3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine: Toa solution of 4-amino-dimethylphenylphosphine oxide (1.6 mmol) and3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH₂Cl₂, is addedtriethylamine (2 mmol). The reaction mixture is allowed to cool to roomtemperature, dissolved in dichloromethane and washed with an aqueoussolution of Na₂CO₃. The dichloromethane extract is dried over MgSO₄ andevaporated. The crude product is purified by Prep-HPLC.

1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine: To asolution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol) in 3 mL of DMFwas added 1-methyl-4-(piperidin)piperazine (0.536 g, 2.92 mmol) andpotassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120°C. for 18 h. The mixture was basified with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic layer waspurified by chromatography to give final product as yellow solid (0.95g, 95% yield). MS/ES+: m/z=334.

2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline: The asolution of1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g,0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladiumon carbon (0.060 g). The hydrogenation was finished under 30 psi after 4h. The mixture was passed through Celite to a flask containing HCl inethanol. Concentration of the filtrate gave the final product (0.15 g,88% yield). MS/ES+: m/z=334.

6-chloro-N⁵-[4-(dimethylphosphoryl)phenyl]-N³-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine (0.7mmol), 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline(0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48hours in 2-propanol. The reaction mixture is allowed to cool to roomtemperature, dissolved in dichloromethane and washed with an aqueoussolution of Na₂CO₃. The dichloromethane extract is dried over MgSO₄ andevaporated. The crude product is purified by Prep-HPLC.

Example 1096-chloro-N³-[6-(dimethylphosphoryl)-2-methoxypyridin-3-y]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine: To a solution of6-bromo-2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (77.2 mg, 39% yield).

6-chloro-N³-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (0.7 mmol) andcamphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in2-propanol. The reaction mixture is allowed to cool to room temperature,dissolved in dichloromethane and washed with an aqueous solution ofNa₂CO₃. The dichloromethane extract is dried over MgSO₄ and evaporated.The crude product is purified by Prep-HPLC.

Example 1106-chloro-N³-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine: To a solution of5-bromo-3-methoxypyrazin-3-ylamine (0.204 g, 1.00 mmol) in 4 mL DMF wasadded dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate(11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassiumphosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-10% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (126 mg, 63% yield).

6-chloro-N³-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (0.7 mmol) andcamphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in2-propanol. The reaction mixture is allowed to cool to room temperature,dissolved in dichloromethane and washed with an aqueous solution ofNa₂CO₃. The dichloromethane extract is dried over MgSO₄ and evaporated.The crude product is purified by Prep-HPLC.

Example 111N⁵-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N³-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline

4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene: At 0 degree, to astirring solution of 4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) inDCM was added Sodium propane-2-thiolate (2.0 g, 20 mmol) in twoportions. The reaction mixture was warmed to room temperature andstirred overnight. The reaction mixture was filtered through a syringefilter. The product was isolated by prep-HPLC (water/Acetonitrile) as abright yellow solid (0.8 g, 2.9 mmol, 32% yield).

4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene: To a stirring solutionof 4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene (0.8 g, 2.9 mmol) inAcetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous solution,0.6 mL, 5.8 mmol). The reaction mixture was heated to 110 degrees C. for2 hours in oil bath. The reaction mixture was treated with saturatedSodium Sulfide aqueous solution and basified with saturated sodiumbicarbonate solution. The mixture was extracted with Ethyl Acetate andthe combined organic layers were dried over sodium sulfate. The organicsolvent was removed under reduced pressure and the residue was used forthe next step reaction without further purification.

Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide: To astirring solution of 4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene(0.44 g, 1.6 mmol) and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1mL of DMF, was added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc)₂(18 mg, 0.08 mmol), Xantphos (55 mg, 0.10 mmol). The reaction mixturewas stirred at 110 degrees C. overnight. The reaction mixture was cooledto room temperature and filtered through celite. The desired product wasisolated through prep-HPLC to yield a brownish yellow solid (0.24 g, 55%yield).

4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: To a solution ofdimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g,0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24 mg) andstirred under hydrogen overnight. The reaction mixture was filtered andthe organic solvent was removed under reduced pressure. The residue waspurified by prep-HPLC to yield 100 mg of desired product (50% yield).

5-chloro-N-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazin-3-amine:To a solution of 5-chloro-6-methyl-1,2,4-triazin-3-amine (2.00 mmol) in8 mL toluene is added4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline (2.20 mmol),palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120mmol), and cesium carbonate (2.20 mmol). The mixture is purged withnitrogen, and can be subjected to microwaves at 100° C. until formationof the desired product. The reaction mixture can then be concentratedand purified by silica gel chromatography.

N⁵-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N³-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazine-3,5-diamine:To a solution of5-chloro-N-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazin-3-amine(0.035 g, 0.11 mmol) in 1 mL of 2-methoxyethanol in a vial is added2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]aniline (0.020 g, 0.085mmol). The vial is sealed and the reaction is heated at 90° C. untilformation of the desired compound. The reaction is then quenched with 1NNaOH solution and the solution extracted ethyl acetate. The organiclayers are combined, washed with saturated sodium chloride solution,dried with sodium sulfate, filtered and concentrated. The crude residueis purified by silica gel chromatography.

Example 1126-chloro-N³-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

5-(Dimethylphosphoryl)-2-methoxyaniline: To a solution of5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.365 g, 85% yield).

6-chloro-N³-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 104: 0.7 mmol),5-(Dimethylphosphoryl)-2-methoxyaniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 1136-chloro-N³-[4-(dimethylphosphoryl)-2-methylphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(Dimethylphosphoryl)-2-methylaniline: To a solution of4-bromo-2-methylaniline (0.372 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.313 g, 85% yield).

6-chloro-N³-[4-(dimethylphosphoryl)-2-methylphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:Amixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(Dimethylphosphoryl)-2-methylaniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃.

The dichloromethane extract is dried over MgSO₄ and evaporated. Thecrude product is purified by Prep-HPLC.

Example 1146-chloro-N³-[4-(dimethylphosphoryl)-2-ethylphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(Dimethylphosphoryl)-2-ethylaniline: To a solution of4-bromo-2-ethylaniline (0.400 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.308 g, 78% yield).

6-chloro-N³-[4-(dimethylphosphoryl)-2-ethylphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(Dimethylphosphoryl)-2-ethylaniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 1156-chloro-N³-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline: To a solution of4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF wasadded dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate(22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl inmethanol to afford the desired product as its hydrochloride salt (0.573g, 98% yield).

6-chloro-N³-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(Dimethylphosphoryl)-2-(trufluoroethoxy)aniline (0.7 mmol) andcamphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in2-propanol. The reaction mixture is allowed to cool to room temperature,dissolved in dichloromethane and washed with an aqueous solution ofNa₂CO₃. The dichloromethane extract is dried over MgSO₄ and evaporated.The crude product is purified by Prep-HPLC.

Example 1166-chloro-N³-[2-chloro-4-(dimethylphosphoryl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

2-Chloro-4-(dimethylphosphoryl)aniline: To a solution of2-chloro-4-iodoaniline (0.507 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (0.340 g, 83% yield).

6-chloro-N³-[2-chloro-4-(dimethylphosphoryl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),2-Chloro-4-(dimethylphosphoryl)aniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 1176-chloro-N³-[4-(dimethylphosphoryl)-2-fluorophenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(Dimethylphosphoryl)-2-fluoroaniline: To a solution of4-bromo-2-fluoroaniline (0.380 g, 2.00 mmol) in 8 mL DMF was addeddimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassiumphosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen,and subjected to microwaves at 150° C. for 20 minutes. The reactionmixture was concentrated and purified by silica gel chromatography(0-20% 7N ammonia in methanol:dichloromethane) to afford the desiredproduct (73.5 mg, 20% yield).

6-chloro-N³-[4-(dimethylphosphory0-2-fluorophenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(Dimethylphosphoryl)-2-fluoroaniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 1186-chloro-N³-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline

Diethyl (3-methoxy-4-nitrophenyl)phosphonate: To a solution of5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was addeddiethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27mmol), XANTPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g,5.86 mmol). The mixture was purged with nitrogen, and subjected tomicrowaves at 150° C. for 20 minutes. The reaction mixture wasconcentrated and purified by silica gel chromatography (0-45% ethylacetate:heptane) to afford the desired product (0.504 g, 33% yield).

(3-methoxy-4-nitrophenyl)phosphonic dichloride: To a solution of diethyl(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL DMFwas added thionyl chloride (5.7 mL, 78.5 mmol). The reaction flask wasequipped with a reflux condenser and the mixture was heated to reflux.After 2 h at reflux, the reaction was cooled to room temperature andconcentrated in vacuo. The crude oil was redissolved in CH₂Cl₂ andheptane was added to precipitate the desired compound. The clearsolution was decanted and the precipitate was collected and dried toafford the desired compound as a white solid (1.39 g, 33% yield).

Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide: To a solution of(3-methoxy-4-nitrophenyl)phosphonic dichloride (1.39 g, 5.15 mmol) in 15mL THF at −78° C. under nitrogen was slowly added vinylmagnesium bromide(10.3 mL, 1.0 M in THF). After the addition was complete, the reactionstirred at −78° C. for an additional hour. The cold reaction mixture wasquenched by the addition of saturated NH₄Cl (20 mL) and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed with 1 MNaOH, brine, and dried over MgSO₄. The organic extracts were filteredand concentrated to provide Diethenyl(3-methoxy-4-nitrophenyl)phosphaneoxide (0.982 g, 75%).

1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide:Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol),ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) weredissolved in 50% aqueous THF (5 mL) and heated to 105° C. undernitrogen. After one hour, another portion of benzylamine was added tothe reaction mixture. The reaction mixture was refluxed for anadditional 2 h, and then cooled to room temperature. The reactionmixture was partitioned between saturated aqueous NaHCO₃ and CH₂Cl₂. Theaqueous phase was washed once with CH₂Cl₂ and the organic layers werecombined. The organic extracts were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (0-10% 7N ammonia in methanol:dichloromethane) to affordthe compound (0.267 g, 46% yield).

4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline: To asolution of 1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane4-oxide (0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with aseptum, evacuated, and refilled with hydrogen. The flask was equippedwith a hydrogen balloon and the reaction stirred for 3 h. The flask wasthen evacuated and refilled with nitrogen. The reaction mixture wasfiltered through Celite and concentrated to provide the crude compoundas the hydrochloride salt, which was used without purification.

6-chloro-N³-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol)and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in2-propanol. The reaction mixture is allowed to cool to room temperature,dissolved in dichloromethane and washed with an aqueous solution ofNa₂CO₃. The dichloromethane extract is dried over MgSO₄ and evaporated.The crude product is purified by Prep-HPLC.

Example 1196-chloro-N³-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline

1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide: To a solution ofmethylphosphonic dischloride (10.0 g, 75.2 mmol) in CH₂Cl₂ at −78° C.,was added vinylmagnesium bromide (175 mL, 1.0 M in THF) via additionfunnel over 4 h. The solution was warmed to 0° C. and quenched with aminimum amount of saturated NH₄Cl. The mixture was filtered through apad of silica gel and silica was extracted with 10% 7N ammonia inmethanol:dichloromethane. The solution was concentrated under reducedpressure to afford methyl divinyl phosphine oxide as a viscous, yellowoil that was used without purification.

A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) andbenzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated atreflux for 16 h. The reaction mixture was concentrated in vacuo and theresidue was purified by silica gel chromatography (0-10% 7N ammonia inmethanol:dichloromethane) to afford1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g,70% yield).

4-methyl-[1,4]azaphosphinane-4-oxide: A flask was charged with1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol) and10% Pd/C (100 mg). The flask was evacuated and filled with nitrogen.Anhydrous methanol (18 mL) was added to the flask and the flask wasequipped with a reflux condenser with a nitrogen inlet. Ammonium formate(2.25 g, 35.8 mmol) was added in one portion at room temperature. Theresulting mixture was stirred at reflux for 2 h. The reaction wasfiltered through a Celite pad and the Celite was washed with 2×5 mLmethanol. The combined filtrate and washing was evaporated in vacuo. Thecrude residue was purified by silica gel chromatography (0-10% 7Nammonia in methanol:dichloromethane) to afford4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%yield).

1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide: Amixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol),5-fluoro-2-nitroanisole (340 mg, 2.00 mmol), K₂CO₃ (345 mg, 2.50 mmol),and DMF (5 mL) was heated to 50° C. After 2 h, the reaction mixture wasconcentrated and purified by silica gel chromatography (0-5% 7N ammoniain methanol:dichloromethane) to afford1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as abright yellow solid (272 mg, 96% yield).

2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline: To apressure vessel was added1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide (272 mg,0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The vessel wasconnected to a Parr apparatus, evacuated, and refilled with nitrogen.The vessel was then evacuated and filled with hydrogen gas to a pressureof 50 psi. The reaction mixture was shaken under 50 psi for 4 h. Themixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a graysolid (211 mg, 87% yield).

6-chloro-N³-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol)and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in2-propanol. The reaction mixture is allowed to cool to room temperature,dissolved in dichloromethane and washed with an aqueous solution ofNa₂CO₃. The dichloromethane extract is dried over MgSO₄ and evaporated.The crude product is purified by Prep-HPLC.

Example 120:6-chloro-N³-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline

tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate: Asolution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) washeated at reflux for 16 h. The reaction mixture was concentrated invacuo and the residue was purified by silica gel chromatography (0-10%7N ammonia in methanol:dichloromethane) to afford the desired compoundas a white solid (178 mg, 38% yield).

1-[1-(3-methoxy-4-nitrophenl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide: To a stirring solution of tert-butyl4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178mg, 0.563 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (0.5mL). After 20 min, the solution was concentrated and the resultingresidue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16mmol) was added portionwise to the stirring solution followed by5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture washeated to 50° C. After 2 h, the reaction mixture was concentrated andthe residue was purified by silica gel chromatography (0-10% 7N ammoniain methanol:dichloromethane) to afford the compound as a bright yellowsolid (176 mg, 86% yield).

2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline:To a pressure vessel was added1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). Thevessel was connected to a Parr apparatus, evacuated, and refilled withnitrogen. The vessel was then evacuated and filled with hydrogen gas toa pressure of 50 psi. The reaction mixture was shaken under 50 psi for 4h. The mixture was filtered through Celite to a flask containing HCl inethanol. Concentration of the filtrate afforded the compound as a graysolid (178 mg, 98% yield).

6-chloro-N³-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline(0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48hours in 2-propanol. The reaction mixture is allowed to cool to roomtemperature, dissolved in dichloromethane and washed with an aqueoussolution of Na₂CO₃. The dichloromethane extract is dried over MgSO₄ andevaporated. The crude product is purified by Prep-HPLC.

Example 1216-chloro-N³-[4-(diethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine

4-(Diethylphosphoryl)-2-methoxyaniline

To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mLDMF was added diethylphosphine oxide (0.0730 g, 0.544 mmol), palladiumacetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), andpotassium phosphate (0.116 g, 0.544 mmol). The mixture was purged withnitrogen, and subjected to microwaves at 150° C. for 20 minutes. Thereaction mixture was concentrated and purified by silica gelchromatography (0-12% 7N ammonia in methanol:dichloromethane) and thefractions were concentrated. The residue was acidified with 2.5 M HCl inethanol and the solution was concentrated to provide4-(diethylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132g, 91% yield).

6-chloro-N³-[4-(diethylphosphoryl)-2-methoxyphenyl]-N⁵-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine:A mixture of3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine(prepared as in Example 106: 0.7 mmol),4-(Diethylphosphoryl)-2-methoxyaniline (0.7 mmol) and camphorsulfonicacid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. Thereaction mixture is allowed to cool to room temperature, dissolved indichloromethane and washed with an aqueous solution of Na₂CO₃. Thedichloromethane extract is dried over MgSO₄ and evaporated. The crudeproduct is purified by Prep-HPLC.

Example 122 Synthesis of Compound 5:

Compound 5 can be synthesized as outlined in Scheme 122 (below).

Synthesis of 1:

To a solution of 2-iodoaniline (1.0 eq) and dimethylphosphine oxide (1.1eq) in DMF were added potassium phosphate (1.1 eq), palladiumacetate/Xantphos (catalytic). The reaction was stirred at 150° C. for 3hours and cooled to room temperature. The solvent was evaporated and theresidue was worked up with DCM/water. The crude product was purifiedwith a column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80% yield).

Synthesis of 2:

2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate(3.14 eq) in DMF were stirred at 60° C. for 5 hours and then cooled tor.t. The mixture was filtered and the filtrate was concentrated. Theresidue was purified with ISCO (DCM/MeOH 20:1) to give 2 as a yellowsolid (61% yield).

Synthesis of 3:

5-Fluoro-2-nitroanisole (1.0 eq), 1-methyl-4-(piperidin-4-yl)piperazine(1.0 eq), and potassium carbonate (2.0 eq) in DMF were stirred at 120°C. for 6 hours and then cooled to r.t. The mixture was filtered andevaporated. The crude product was crystallized from ethanol to give 3 asa yellow solid (72% yield).

Synthesis of 4:

Palladium on activated carbon was added to a solution of 3 in ethanolunder nitrogen. The suspension was then shaken under hydrogen (50 psi)for 3 hours. The mixture was filtered and the filtration was evaporatedto give 4 as a purple solid in a quantitative yield.

Synthesis of 5:

A solution of 2 (1.0 eq), 4 (1.4 eq), and 2.5 M HCl in ethanol (excess)in 2-methoxyethanol was sealed and heated at 120° C. with stirring for5.5 hours and then cooled to r.t. The reaction was repeated 5 times andcombined. The mixture was filtered and evaporated. Saturated Na₂CO₃ wasadded, followed by DCM with stirring strongly. The layers were separatedand the aqueous layer was extracted with DCM. The organics were dried,evaporated and chromatographed [EtOAc/MeOH (7M ammonia) 20:1] to give ayellow solid. EtOAc was added and the suspension was refluxed for 30minutes. After cooled to r.t., filtration gave a solid, which wasdissolved in DCM, filtered, and evaporated to afford 5 as an off-whitesolid (66% yield).

Example 123 Biological Evaluation of Compounds

Compounds of the invention are evaluated in a variety of assays todetermine their biological activities. For example, compounds of theinvention can be tested for their ability to inhibit various proteinkinases of interest. Some of the compounds tested displayed potentnanomolar activity against the following kinases: ALK and c-Met.Furthermore, some of these compounds were screened for antiproliferativeactivity in the human Karpas-299 and in the human SU-DHL-1 lymphoma celllines and demonstrated activity on the range of 1-100 nM. The compoundscan also be evaluated for their cytotoxic or growth inhibitory effectson tumor cells of interest, e.g., as described in more detail below andas shown above for some representative compounds. See e.g., WO03/000188, pages 115-136, the full contents of which are incorporatedherein by reference.

Some representative compounds of the invention are depicted below:

The following representative compounds were synthesized and tested forkinase inhibition against a panel of kinases and some also tested invarious cell lines. Many of the compounds were found to be active in invitro assays.

Kinase Inhibition

More specifically, the compounds described herein are screened forkinase inhibition activity as follows. Kinases suitable for use in thefollowing protocol include, but are not limited to: ALK, Jak2, b-Raf,c-Met, Tie-2, FLT3, Abl, Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk,EGFR, ErbB2, Kdr, FLT1, Tek, InsR, and AKT.

Kinases are expressed as either kinase domains or full length constructsfused to glutathione S-transferase (GST) or polyHistidine tagged fusionproteins in either E. coli or Baculovirus-High Five expression systems.They are purified to near homogeneity by affinity chromatography aspreviously described (Lehr et al., 1996; Gish et al., 1995). In someinstances, kinases are co-expressed or mixed with purified or partiallypurified regulatory polypeptides prior to measurement of activity.

Kinase activity and inhibition can be measured by established protocols(see e.g., Braunwalder et al., 1996). In such cases, the transfer of³³PO₄ from ATP to the synthetic substrates poly(Glu, Tyr) 4:1 orpoly(Arg, Ser) 3:1 attached to the bioactive surface of microtiterplates is taken as a measure of enzyme activity. After an incubationperiod, the amount of phosphate transferred is measured by first washingthe plate with 0.5% phosphoric acid, adding liquid scintillant, and thencounting in a liquid scintillation detector. The IC₅₀ is determined bythe concentration of compound that causes a 50% reduction in the amountof ³³P incorporated onto the substrate bound to the plate.

Other methods relying upon the transfer of phosphate to peptide orpolypeptide substrate containing tyrosine, serine, threonine orhistidine, alone, in combination with each other, or in combination withother amino acids, in solution or immobilized (i.e., solid phase) arealso useful.

For example, transfer of phosphate to a peptide or polypeptide can alsobe detected using scintillation proximity, Fluorescence Polarization andhomogeneous time-resolved fluorescence. Alternatively, kinase activitycan be measured using antibody-based methods in which an antibody orpolypeptide is used as a reagent to detect phosphorylated targetpolypeptide.

For additional background information on such assay methodologies, seee,.g., Braunwalder et al., 1996, Anal. Biochem. 234(1):23; Cleaveland etal., 1990, Anal Biochem. 190(2):249 Gish et al. (1995). Protein Eng.8(6):609 Kolb et al. (1998). Drug Discov. Toda V. 3:333 Lehr et al.(1996). Gene 169(2):27527-87 Seethala et al. (1998). Anal Biochem.255(2):257 Wu et al. (2000).

The inhibition of ALK tyrosine kinase activity can be demonstrated usingknown methods. For example, in one method, compounds can be tested fortheir ability to inhibit kinase activity of baculovirus-expressed ALKusing a modification of the ELISA protocol reported for trkA in Angeles,T. S. et al., Anal. Biochem. 1996, 236, 49-55, which is incorporatedherein by reference. Phosphorylation of the substrate, phopholipaseC-gamma (PLC-γ) generated as a fusion protein withglutathione-S-transferase (GST) as reported in rotin, D. et al., EMBO J.1992, 11, 559-567, which is incorporated by reference, can be detectedwith europium-labeled anti-phosphotyrosine antibody and measured bytime-resolved fluorescence (TRF). In this assay, 96-well plate is coatedwith 100 μL/well of 10 μg/mL substrate (phospholipase C-γ intris-buffered saline (TBS). The assay mixture (total volume=100 μL/well)consisting of 20 nM HEPES (pH 7.2, 1 μMATP (K_(m) level), 5 nM MnCl₂,0.1% BSA, 2.5% DMSO, and various concentrations of test compound is thenadded to the assay plate. The reaction is initiated by adding the enzyme(30 ng/mL ALK) and is allowed to proceed at 37 degrees C. for 15minutes. Detection of the phosphorylated product can be performed byadding 100 μL/well of Eu-N1 labeled PT66 antibody (Perkim Elmer#AD0041). Incubation at 37 degrees C then proceeds for one hour,followed by addition of 100 □L enhancement solution (for example Wallac#1244-105). The plate is gently agitated and after thirty minutes, thefluorescence of the resulting solution can be measured (for exampleusing EnVision 2100 (or 2102) multilabel plate reader from PerkinElmer).

Data analysis can then be performed. IC₅₀ values can be calculated byplotting percent inhibition versus log₁₀ of concentration of compound.

The inhibition of ALK tyrosine kinase activity can also be measuredusing the recombinant kinase domain of the ALK in analogy to VEDG-Rkinase assay described in J. Wood et al., Cancer Res 2000, 60,2178-2189. In vitro enzyme assays using GST-ALK protein tyrosine kinasecan be performed in 96-well plate as a filter binding assay in 20mMTris.HCl, pH 7.5, 3 mM MgCl₂, 10 mM MnCl₂, 1 nM DTT, 0.1 μCi/assay(=30μL) [γ-³³P]-ATP, 2 μM ATP, 3 μg/mL poly (Glu, tyr 4:1) Poly-EY (sigmaP-0275), 1% DMSO, 25 ng ALK enzyme. Assays can be incubated for 10 min,at ambient temperature. Reactions can be terminated by adding 50 μL of125 mM EDTA, and the reaction mixture can be transferred onto a MAIPMultiscreen plate (Millipore, Bedford, Mass.) previously wet withmethanol, and rehydrated for 5 minutes with water. Following washing(0.5% H₃PO₄), plates can be counted in a liquid scintillation counter.IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition.

Cell-Based Assays

Certain compounds of the invention have also been demonstrated cytotoxicor growth inhibitory effects on tumor and other cancer cell lines andthus may be useful in the treatment of cancer and other cellproliferative diseases. Compounds are assayed for anti-tumor activityusing in vivo and in vitro assays which are well known to those skilledin the art. Generally, initial screens of compounds to identifycandidate anti-cancer drugs are performed in cellular assays. Compoundsidentified as having anti-proliferative activity in such cell-basedassays can then be subsequently assayed in whole organisms foranti-tumor activity and toxicity. Generally speaking, cell-based screenscan be performed more rapidly and cost-effectively relative to assaysthat use whole organisms. For purposes of the invention, the terms“anti-tumor” and “anti-cancer” activity are used interchangeably.

Cell-based methods for measuring antiproliferative activity are wellknown and can be used for comparative characterization of compounds ofthe invention. In general, cell proliferation and cell viability assaysare designed to provide a detectable signal when cells are metabolicallyactive. Compounds may be tested for antiproliferative activity bymeasuring any observed decrease in metabolic activity of the cells afterexposure of the cells to compound. Commonly used methods include, forexample, measurement of membrane integrity (as a measure of cellviability) (e.g. using trypan blue exclusion) or measurement of DNAsynthesis (e.g. by measuring incorporation of BrdU or 3H-thymidine).

Some methods for assaying cell proliferation use a reagent that isconverted into a detectable compound during cell proliferation.Particularly preferred compounds are tetrazolium salts and includewithout limitation MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;Sigma-Aldrich, St. Louis, Mo.), MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium),XTT(2,3-bis(2-Methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide),INT, NBT, and NTV (Bernas et al. Biochim Biophys Acta 1451(1):73-81,1999). More commonly used assays utilizing tetrazolium salts detect cellproliferation by detecting the product of the enzymatic conversion ofthe tetrazolium salts into blue formazan derivatives, which are readilydetected by spectroscopic methods (Mosman. J. Immunol. Methods.65:55-63, 1983).

Other methods for assaying cell proliferation involve incubating cellsin a desired growth medium with and without the compounds to be tested.Growth conditions for various prokaryotic and eukaryotic cells arewell-known to those of ordinary skill in the art (Ausubel et al. CurrentProtocols in Molecular Biology. Wiley and Sons. 1999; Bonifacino et al.Current Protocols in Cell Biology. Wiley and Sons. 1999 bothincorporated herein by reference). To detect cell proliferation, thetetrazolium salts are added to the incubated cultured cells to allowenzymatic conversion to the detectable product by active cells. Cellsare processed, and the optical density of the cells is determined tomeasure the amount of formazan derivatives. Furthermore, commerciallyavailable kits, including reagents and protocols, are available forexamples, from Promega Corporation (Madison, Wis.), Sigma-Aldrich (St.Louis, Mo.), and Trevigen (Gaithersburg, Md.).

In addition, a wide variety of cell types may be used to screencompounds for antiproliferative activity, including the following celllines, among others: COLO 205 (colon cancer), DLD-1 (colon cancer),HCT-15 (colon cancer), HT29 (colon cancer), HEP G2 (Hepatoma), K-562(Leukemia), A549 (Lung), NCI-H249 (Lung), MCF7 (Mammary), MDA-MB-231(Mammary), SAOS-2 (Osteosarcoma), OVCAR-3 (Ovarian), PANC-1 (Pancreas),DU-145 (Prostate), PC-3 (Prostate), ACHN (Renal), CAKI-1 (Renal), MG-63(Sarcoma).

While the cell line is preferably mammalian, lower order eukaryoticcells such as yeast may also be used to screen compounds. Preferredmammalian cell lines are derived from humans, rats, mice, rabbits,monkeys, hamsters, and guinea pigs since cells lines from theseorganisms are well-studied and characterized. However, others may beused as well.

Suitable mammalian cell lines are often derived from tumors. Forexample, the following tumor cell-types may be sources of cells forculturing cells: melanoma, myeloid leukemia, carcinomas of the lung,breast, ovaries, colon, kidney, prostate, pancreas and testes),cardiomyocytes, endothelial cells, epithelial cells, lymphocytes (T-celland B cell), mast cells, eosinophils, vascular intimal cells,hepatocytes, leukocytes including mononuclear leukocytes, stem cellssuch as haemopoetic, neural, skin, lung, kidney, liver and myocyte stemcells (for use in screening for differentiation and de-differentiationfactors), osteoclasts, chondrocytes and other connective tissue cells,keratinocytes, melanocytes, liver cells, kidney cells, and adipocytes.Non-limiting examples of mammalian cells lines that have been widelyused by researchers include HeLa, NIH/3T3, HT1080, CHO, COS-1, 293T,WI-38 and CV1/EBNA-1.

Other cellular assays may be used which rely upon a reporter gene todetect metabolically active cells. Non-limiting examples of reportergene expression systems include green fluorescent protein (GFP), andluciferase. As an example of the use of GFP to screen for potentialantitumor drugs, Sandman et al. (Chem Biol. 6:541-51; incorporatedherein by reference) used HeLa cells containing an inducible variant ofGFP to detect compounds that inhibited expression of the GFP, and thusinhibited cell proliferation.

An example of cell-based assay is shown as below. The cell lines thatcan be used in the assay are Ba/F3, a murine pro-B cell line, which hasbeen stably transfected with an expression vector pClneo™ (PromegaCorp., Madison Wis.) coding for NPM-ALK and subsequent selection of G418resistant cells. Non-transfected Ba/F3 cells depend on IL-3 for cellsurvival. In constrast NPM-ALK expressing Ba/F3 cells (namedBa/F3-NPM-ALK) can proliferate in the absence of IL-3 because theyobtain proliferative signal through NMP-ALK kinase. Putative inhibitorsof NPM-ALK kinase therefore abolish the growth signal and result inantiproliferative activity. The antiproliferative activity of inhibitorsof the NPM-ALK kinase can however be overcome by addition of IL-3 whichprovides growth signals through an NPM-ALK independent mechanism. For ananalogous cell system using FLT3 kinase see E. Weisberg et al. Cancercell, 2002, 1, 433-443. The inhibitory activity of the compounds offormula I can be determined as follows: BaF3-NPM-ALK cells(15,000/microtitre plate well) can be transferred to a 96-wellmicrotitre plates. The test compound (dissolved in DMSO) is then addedin a series of concentrations (dilution series) in such a manner thatthe final concentration of DMSO is not greater than 1% (v/v). After theaddition, the plates can be incubated for two days during which thecontrol cultures without test compound are able to undergo twocell-division cycles. The growth of BaF3-NPM-ALK cells can be measuredby means of Yopro™ staining (T Idziorek et al., J. Immunol. Methods1995, 185, 249-258). 25 μL of lysis buffer consisting of 20 mM sodiumcitrate, pH 4.0, 26.8 nM sodium chloride, 0.4% NP40, 20 mM EDTA and 20mM is added into each well. Cell lysis is completed within 60 minutes atroom temperature and total amount of Yopro bound to DNA is determined bymeasurement using for example a CytoFluor II 96-well reader (PerSeptiveBiosystems). The IC₅₀ can be determined by a computer aided system usingthe formula:

IC₅₀=[(ABS _(test) −ABS _(start))/(ABS _(control) −ABS _(start))]×100

in which ABS is absorption. The IC₅₀ value in such an experiment isgiven as that concentration of the test compound in question thatresults in a cell count that is 50% lower than that obtained using thecontrol without inhibitor.

The antiproliferative action of compounds of the invention can also bedetermined in the human KARPAS-299 lymphoma cell line by means of animmunoblot as described in W G Dirks et al. Int. J. Cancer 2002, 100,49-56., using the methodology described above for the BaF3-NPM-ALK cellline.

In another example, antiproliferative activity can be determined usingKARPAS-299 lumphoma cell line in the following procedure: Compounds ofthe invention were incubated with the cells for 3 days, and the numberof viable cells in each well was measured indirectly using an MTStetrazolium assay (Promega). This assay is a colorimetric method fordetermining the number of viable cells through measurement of theirmetabolic activity. For example the detection of the product of theenzymatic conversion of tetrazolium salts into blue formazan derivativesis achieved by measuring absorbance at 490 nm using a plate reader. 40μL of the MTS reagent was added to all wells except the edge wells andthen the plates were returned to the incubator at 37° C. for 2 hours.The absorbance in each well was then measured at 490 nm using a WallacVictor²V plate reader. The IC₅₀ was calculated by determining theconcentration of compound required to decrease the MTS signal by 50% inbest-fit curves using Microsoft XLfit software, by comparing withbaseline, the DMSO control, as 0% inhibition.

Compounds identified by such cellular assays as having anti-cellproliferation activity are then tested for anti-tumor activity in wholeorganisms. Preferably, the organisms are mammalian. Well-characterizedmammalians systems for studying cancer include rodents such as rats andmice. Typically, a tumor of interest is transplanted into a mouse havinga reduced ability to mount an immune response to the tumor to reduce thelikelihood of rejection. Such mice include for example, nude mice(athymic) and SCID (severe combined immunodeficiency) mice. Othertransgenic mice such as oncogene containing mice may be used in thepresent assays (see for example U.S. Pat. Nos. 4,736,866 and 5,175,383).For a review and discussion on the use of rodent models for antitumordrug testing see Kerbel (Cancer Metastasis Rev. 17:301-304, 1998-99).

In general, the tumors of interest are implanted in a test organismpreferably subcutaneously. The organism containing the tumor is treatedwith doses of candidate anti-tumor compounds. The size of the tumor isperiodically measured to determine the effects of the test compound onthe tumor. Some tumor types are implanted at sites other thansubcutaneous sites (e.g. intraperitoneal sites) and survival is measuredas the endpoint. Parameters to be assayed with routine screening includedifferent tumor models, various tumor and drug routes, and dose amountsand schedule. For a review of the use of mice in detecting antitumorcompounds see Corbett et al. (Invest New Drugs. 15:207-218, 1997;incorporated herein by reference).

Results

A wide variety of compounds of this invention were found to potentlyinhibit a number of important kinase targets. Many exhibited IC50'sunder 100 nM, and in many cases under 10 nM and in some cases under 1 nMwhen tested as inhibitors of the kinase, ALK, for instance. Thoseincluded compounds containing the phosphine oxide moiety as an R^(a) orR^(e) substituent as well as compounds in which positions X³ and X⁴ werethe base of a substituted or unsubstituted fused ring which is presentin a number of embodiments. Some compounds were single digit nanomolarinhibitors of a panel of kinases including kinases like ALK, FER, FLT3,FES/FPS, FAK/PTK2, BRK and others. Compounds of the invention of variousstructures were found to exhibit preferences for inhibiting some kinasesover others as well as variations in pharmacokinetic profiles,confirming that this class of compounds is of great interest as a sourceof potential pharmaceutical agents.

To illustrate the foregoing, a varied group of compounds (shown below)were tested and found to have IC50 values under 1 nM when tested againstthe kinase ALK.

Example 21 Pharmaceutical Compositions

Representative pharmaceutical dosage forms of compounds of the invention(the active ingredient being referred to as “Compound”), are providedfor therapeutic or prophylactic use in humans:

(a) Tablet 1 mg/tablet Compound 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% 2.25 w/v paste)Magnesium stearate 3.0

(b) Tablet II mg/tablet Compound 50 Lactose Ph. Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyffolidone 2.25(5% w/v paste) Magnesium stearate 3.0

(c) Tablet III mg/tablet Compound 1.0 Lactose Ph. Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% 0.75 w/v paste)Magnesium stearate 1.0-76

(d) Capsule mg/capsule Compound 10 Lactose Ph. Eur 488.5 Magnesium 1.5

(e) Injection I (50 mg/ml) Compound 5.0% w/v 1M Sodium hydroxidesolution 15.0% v/v  0.1M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100%

(f) Injection II (10 mg/ml) Compound 1.0% w/v Sodium phosphate BP 3.6%w/v 0.1M Sodium hydroxide solution 15.0% v/v  Water for injection to100%

(g) Injection III (1 mg/ml, buffered to pH6) Compound 0.1% w/v Sodiumphosphate BP 2.26% w/v  Citric acid 0.38% w/v  Polyethylene glycol 4003.5% w/v Water for injection to 100%

(h) Aerosol I mg/ml Compound 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0

(i) Aerosol II mg/ml Compound 0.2 Sorbitan trioleate 0.27Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0Dichlorotetrafluoroethane 1094.0

(j) Aerosol III mg/ml Compound 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6

(k) Aerosol IV mg/ml Compound 2.5 Soya lecithin 2.7Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6

(1) Ointment /ml Compound 40 mg Ethanol 300 μl Water 300 μl1-Dodecylazacycloheptan one 50 μl Propylene glycol to 1 ml

These formulations may be prepared using conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, if desired to provide a coating ofcellulose acetate phthalate, for example. The aerosol formulations(h)-(k) may be used in conjunction with standard, metered dose aerosoldispensers, and the suspending agents sorbitan trioleate and soyalecithin may be replaced by an alternative suspending agent such assorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerololeate or oleic acid.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

1. A compound of the formula VIa:

wherein X¹ is NR^(b1) or CR^(b); X³ is NR^(d1) or CR^(d); X⁴ is NR^(e1)or CR^(e); Ring A and Ring E are each an independently selected aryl orheteroaryl ring, the heteroaryl ring being a 5- or 6-membered ringcontaining 1 to 4 heteroatoms selected from N, O and S(O)_(r); eachoccurrence of R^(a), R^(b), R^(d), R^(e), and R^(g) is independentlyselected from the group consisting of halo, —CN, —NO₂, —R¹, —OR²,—O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R²; oralternatively, each R^(a) and R^(g) may also be an independentlyselected moiety, —P(═O)(R³)₂ or a ring system containing the moiety—P(═O)(R³)— as a ring member; R^(b1), R^(d1) and R^(e1) are absent; oralternatively two adjacent substituents selected from R^(d), R^(d1),R^(e), and R^(e1), or two adjacent R^(a) moieties, can form, with theatoms to which they are attached, a fused, 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which contains 0-4heteroatoms selected from N, O and S(O), and which may bear up to foursubstituents; at least one of R^(a) and R^(g) is or contains a moiety,—P(═O)(R³)₂ or a ring system containing the moiety —P(═O)(R³)—as a ringmember; L is 0 or NH; r is 0, 1 or 2; s is 1, 2, 3, 4 or 5; p is 1, 2, 3or 4; each occurrence of Y is independently a bond, —O—, —S— or —NR′—;each occurrence of R¹ and R² is independently H or an alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic or heteroaryl moiety; each occurrence of R³ isindependently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety, ortwo adjacent R³ moieties combine to form a ring system including aphosphorous atom; each occurrence of R^(3a) is independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic, and heteroaryl; alternatively, eachNR¹R² moiety may be a 5-, 6- or 7-membered saturated, partiallysaturated or unsaturated ring, which can be optionally substituted andwhich contains 0-2 additional heteroatoms selected from N, O andS(O)_(r); and each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic moietiesis optionally substituted.
 2. The compound of claim 1 in which X¹ is N.3. The compound of claim 2 in which X³ is N and X⁴ is CR^(e).
 4. Thecompound of claim 2 in which X³ is CR^(d) and X⁴ is CR^(c).
 5. Thecompound of claim 1 in which X¹ is CR^(b).
 6. The compound of claim 5 inwhich X³ is N and X⁴ is CR^(e).
 7. The compound of claim 5 in which X³is CR^(d) and X⁴ is CR^(e).
 8. The compound of any of claim 1, 2, 4, 5or 7 in which R^(d) is selected from Cl, F, C1-C4 alkyl, trihaloalkyl,cycloalkyl, C2-C4 alkenyl, and alkynyl.
 9. The compound of claim 1 inwhich X³ is CR^(d) and X⁴ is CR^(e) wherein R^(d) and R^(e), togetherwith the atoms to which they are attached, form a fused, 5-, 6- or7-membered saturated, partially saturated or unsaturated ring, whichcontains 0-4 heteroatoms selected from N, O and S(O)_(r), and which maybear up to four substituents.
 10. The compound of any of claims 1-9 inwhich s is 1, 2, 3 or 4, and each of the substituents R^(a) isindependently selected from halo, —R¹, —OR², —NR¹R² and —P(═O)(R³)₂,wherein each R¹ and R² moiety may be further substituted orunsubstituted.
 11. The compound of claim 10 in which at least onesubstituent R^(a) is —OR² and R² is selected from C1-C6 alkyl, C1-C6alkenyl, and C2-C6 alkynyl.
 12. The compound of claim 10 or 11 in whichat least one substituent R^(a) is a 5-, 6- or 7-membered heterocyclic or5- or 6-membered heteroaryl moiety, linked to Ring A either directly orby an ether bond, and which may be further substituted with 1-3substituents independently selected from halo, —CN, —NO₂, —R¹, —OR²,—O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R^(3a))₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R²;wherein each Y is independently a bond, —O—, —S— or —NR¹—.
 13. Thecompound of claim 12 in which the heterocyclic or heteroaryl substituentR^(a) is selected from the following:


14. The compound of any of claims 10-13 in which at least onesubstituent R^(a) is —P(═O)(R³)₂ in which each R³ is, independently, aC1-C4 alkyl moiety.
 15. The compound of any of claims 1-14 in which L isNH, Ring E is aryl, and each R^(g) is independently selected from halo,—R¹, —OR², —S(O)_(r)R² and —P(═O)(R³)₂.
 16. The compound of claim 15 inwhich Ring E contains at least one moiety R^(g) in the ortho position,relative to the ring atom attached to L.
 17. The compound of claim 15 inwhich Ring E contains at least one moiety R^(g) in the meta position,relative to the ring atom attached to L.
 18. The compound of claim 15 inwhich Ring E contains at least one moiety R^(g) in the para position,relative to the ring atom attached to L.
 19. The compound of any ofclaims 15-18 in which at least one moiety R^(g) is —P(═O)(R³)₂ and is—P(═O)(R³)₂ is —P(═O)(CH₃)₂ or —P(═O)(CH₂CH₃)₂.
 20. The compound ofclaim 13 in which L is NH; X¹ is N; X³ is CR^(d); X⁴ is CR^(C); Ring Ais aryl and optionally contains up to two additional R^(a) moieties; andRing E is aryl and contains 1-3 R^(g) moieties, one of which being anortho, meta or para —P(═O)(R³)₂ moiety.
 21. A pharmaceutical compositioncontaining a compound of any of claims 1-20 or a pharmaceuticallyaccceptable salt thereof, and a pharmaceutically acceptable vehicle. 22.A method for inhibiting cellular proliferation in a subject, said methodcomprising administering to said subject a compound of any of claims1-20 in an amount effective to inhibit said cellular proliferation.